Esters of 3-(hydroxy or hydroxymethyl)-4-hydroxyphenyl aminomethyl ketones

ABSTRACT

Mono-, di- and tri-esters of 3-(hydroxy or hydroxymethyl)-4-hydroxy-alpha-(aminomethyl)benzyl alcohols, obtained by methods involving reduction of the corresponding mono- and di-ester ketones, are useful for producing sympathomimetic effects, such as bronchodilation, of long duration with low cardiovascular stimulating effect, in warm-blooded mammals.

.[.This application.]. .Iadd.This is an application for reissue ofUnited States Patent 3,904,671, issued Sept. 9, 1975, application Ser.No. 123,834, filed Mar. 12, 1971 which .Iaddend.is acontinuation-in-part of our prior co-pending application Ser. No.812,370, filed Apr. 1, 1969 and now abandoned.

This invention relates to compositions of matter classified in the artof chemistry as esters of 3-(hydroxy orhydroxymethyl)-4-hydroxy-alpha-(aminomethyl)benzyl alcohols, to aprocess and intermediates for the preparation of the same, and to amethod for producing sympathomimetic effects, for instance,bronchodilation, of long duration in warm-blooded animals byadministering said esters.

The invention sought to be patented resides in one of its compositionaspects in the chemical compounds designated as (A) esters of3,4-dihydroxy-alpha-(amino- and N-substituted amino-methyl)benzylalcohols which have in the free base form Formula I hereinbelow, and (B)esters of 3-hydroxymethyl-4-hydroxy-alpha-(amino- and N-substitutedamino-methyl)benzyl alcohols which have in the free base form Formula IIhereinbelow: ##STR1## wherein, in each of Formulas I and II:

R is hydrogen, alkyl having 1-4 carbon atoms or cycloalkyl having 3-6carbon atoms;

R' is hydrogen or alkyl having 1-3 carbon atoms;

Y is an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoylhaving one or two double bonds and having 4-22 carbon atoms,cyclalkyl-C_(n) H_(2n) --CO-- having a total of 4-10 carbon atoms ofwhich 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, oneor two, 1- or 2-adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl,pyridinecarbonyl, or Z--C_(n) H_(2n) --CO-- wherein n is zero, one ortwo and Z is phenyl or phenyl substituted by 1-3 members of the groupconsisting of alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbonatoms, halo, trifluoromethyl, dialkylamino having 2-8 carbon atoms, andalkanoylamino having 1-6 carbon atoms; and

Y¹ and Y² are the same or different and are hydrogen or one of the acylmembers defined by Y, and

wherein in Formula I at least of Y and Y¹ contains no less than fourcarbon atoms when R is tert-butyl or cycloalkyl and no less than sevencarbon atoms when R is hydrogen or alkyl other than tert-butyl; and inFormula II at least one of Y and Y¹ contains no less than four carbonatoms.

These compounds are useful as long-acting sympathomimetic agents whenadministered orally, intratracheally, intraduodenally, or intravenouslyto warm-blooded mammals.

The invention resides in another of its composition aspects in thechemical compounds designated as 3-(Y¹ -O-)-4-(Y-O-)phenyl(R-NH-)(R')methyl ketones having in the free base phenol form theformula ##STR2## and 3-(Y-O-CH₂ -)-4-(Y¹ -O-)phenyl (R-NH-) (R')methylketones having in the free base phenol form the formula ##STR3## .Iadd.wherein, in Formula III, R is tert-butyl or cycloalkyl having 3-6 carbonatoms; and in Formula IV is hydrogen, alkyl having 1-4 carbon atoms, orcycloalkyl having 3-6 carbon atoms; and .Iaddend.wherein, in each ofFormulas III and IV, .[.R,.]. R', Y, and Y¹ have the same significanceindicated hereinabove. These ester ketones are useful as intermediatesin the preparation of the alcohols of Formulas I and II respectivelyhereinabove.

The invention sought to be patented resides in one of its processaspects in the chemical process which comprises reducing an ester ketonehaving in the free base from Formula III or Formula IV hereinabove toproduce an ester alcohol having in free base form Formula I or FormulaII respectively hereinabove wherein Y² is hydrogen.

The invention sought to be patented resides in another of its processaspects in the chemical process which comprises mono- or di-esterifyinga 3,4-dihydroxyphenyl (R-NH-) (R')methyl ketone having in the free baseform the formula ##STR4## or a 3-hydroxymethyl-4-hydroxyphenyl(R-NH-)(R') methyl ketone having in the free base phenol form the formula##STR5## wherein in each of Formulas V and VI, R and R' have the samesignificance indicated hereinabove, .Iadd.in Formulas III and IV.Iaddend.to produce an ester ketone having in the free base form FormulaIII or Formula IV respectively hereinabove.

The invention sought to be patented, in its method aspect, resides inthe method of producing sympathomimetic effects in a warm-blooded mammalwhich comprises administering to said mammal an effective amount of acompound having in the free base form Formula I or Formula IIhereinabove.

When R in the formulas herein is alkyl having 1-4 carbon atoms, thereare included methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl and sec-butyl.

When R in the formulas herein is cycloalkyl having 3-6 carbon atoms,there are included cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

When R' in the formulas herein is alkyl having 1-3 carbon atoms, thereare included methyl, ethyl, n-propyl, and isopropyl.

When Y, Y¹ or Y² in the formulas herein is alkanoyl containing 1-22carbon atoms, there are included both unbranched and branched alkanoyl,for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, 2-methylbutanoyl, pivalyl, 3-methylpentanoyl,3,3-dimethylbutanoyl, 2,2-dimethylpentanoyl, docosanoyl, and7,7-dimethyloctanoyl. The branched alkanoyl groups are preferred overthe unbranched alkanoyl groups.

When Y, Y¹, or Y² in the formulas herein is alkenoyl having one or twodouble bonds and having 4-22 carbon atoms, there are included, forexample, crotonyl, 9-octadecenoyl, 2,5-hexadienoyl, 3,6-octadienoyl,10,13-octadecadienoyl, and 5,13-docosadienoyl.

When Y, Y¹, or Y² in the formulas herein is cycloalkyl-C_(n) H_(2n)--CO--, there are included for example the cycloalkanecarbonyl andcycloalkanealkanoyl groups: cyclopropanecarbonyl,1-methylcyclopropanecarbonyl, cyclopropaneacetyl,alpha-methylcyclopropaneacetyl, 1-methylcyclopropaneacetyl,2-amylcyclopropaneacetyl, cyclopropanepropionyl,alpha-methylcyclopropanepropionyl, 2-isobutylcyclopropanepropionyl,2-hexylcyclopropanecarbonyl, cyclobutanepropionyl,2-methylcyclobutanecarbonyl, 1,3-dimethylcyclobutanecarbonyl,3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl,2,2-dimethyl-3-ethylcyclobutaneacetyl, cyclobutanepropionyl,cyclopentanecarbonyl, 1-methyl-3-isopropylcyclopentanecarbonyl,cyclopentanepropionyl, cyclohexanecarbonyl, cyclohexaneacetyl,4-methylcyclohexaneacetyl, cycloheptanecarbonyl,4-methylcycloheptaneacetyl, and cycloheptanepropionyl.

When Y, Y¹, or Y² in the formulas herein is (phenyl or substitutedphenyl)-C_(n) H_(2n) --CO--, there are included for example benzoyl,phenylacetyl, alphaphenylpropionyl, beta-phenylpropionyl, p-tolyl,m-toluyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl,3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl,m-methylphenylacetyl, p-isobutylphenylacetyl,beta-(p-ethylphenyl)propinyl, p-anisoyl, m-anisoyl, o-anisoyl,m-isopropoxybenzoyl, p-n-butoxybenzoyl, 3-methoxy-4-ethoxybenzoyl,3,4,5-trimethoxybenzoyl, 2,4,6-triethoxybenzoyl, p-methoxyphenylacetyl,m-isobutoxyphenylacetyl, 3,4-diethoxyphenylacetyl,beta-(3,4,5-trimethoxyphenyl)propionyl, o-iodobenzoyl, m-bromobenzoyl,p-chlorobenzoyl, p-fluorobenzoyl, 2-bromo-4-chlorobenzoyl,2,4,6-trichlorobenzoyl, p-chlorophenylacetyl,alpha-(m-bromophenyl)propionyl, p-trifluoromethylbenzoyl,2,4-di(trifluoromethyl)benzoyl, m-trifluoromethylphenylacetyl,beta-(p-trifluoromethylphenyl)propionyl, 2-methyl-4-methoxybenzoyl,3-chloro-4-ethoxybenzoyl, beta-(3-methyl-4-chlorophenyl)propionyl,p-dimethylaminobenzoyl, m-diethylaminobenzoyl, p-dibutylaminobenzoyl,p-(N-methyl-N-ethylamino)benzoyl, o-acetamidobenzoyl,m-propionamidobenzoyl, p-hexanoylaminobenzoyl,3-chloro-4-acetamidophenylacetyl, and p-acetamidophenylpropionyl.

When Y, Y¹ or Y² in the formulas herein is naphthalenecarbonyl, thereare included 1-naphthalenecarbonyl and 2-naphthalenecarbonyl.

When Y, Y¹, or Y² in the formulas herein is pyridinecarbonyl, there areincluded picolinoyl (2-pyridinecarbonyl), nicotinoyl(3-pyridinecarbonyl), and isonicotinoyl (4-pyridinecarbonyl).

As provided above, in Formula I when R is tert-butyl or cycloalkyl, nomore than one of Y and Y¹ contains less than four carbon atoms; and whenR is hydrogen or alkyl other than tert-butyl, no more than one of Y andY¹ contains less than seven carbon atoms. In Formula II at least one ofY and Y¹ contains no less than four carbon atoms.

Due to the presence of the basic amino grouping, the free base forms ofthe final products represented by Formulas I and II and also of theintermediates represented by Formulas III and IV react with organic andinorganic acids to form acid-addition salts. The acid-addition saltforms are prepared from any organic or inorganic acid. They are obtainedin conventional fashion, for instance either by direct mixing of thebase with the acid, or, when this is not appropriate, by dissolvingeither or both of the base and the acid separately in water or anorganic solvent and mixing the two solutions, or by dissolving both thebase and the acid together in a solvent. The resulting acid-additionsalt is isolated by filtration, if it is insoluble in the reactionmedium, or by evaporation of the reaction medium to leave theacid-addition salt as a residue. The acid moieties or anions in thesesalt forms are in themselves neither novel nor critical and thereforecan be any acid anion or acid-like substance capable of salt formationwith the base.

Representative acids for the formation of the acid-addition saltsinclude formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaricacid, succinic acid, succinamic acid, tannic acid, glutamic acid,tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid,glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin,benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid,anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, pamoic acid,3-hydroxy-2-naphtholic acid, picric acid, quinic acid, tropic acid,3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonicacid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid,acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid,hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoricacid, arsenic acid, and the like.

All of the acid-addition salts are useful as sources of the free baseform, by reaction with an inorganic base. It will thus be appreciatedthat if one or more of the characteristics, such as solubility,molecular weight, physical appearance, toxicity, or the like of a givenbase or acid-addition salt thereof render that form unsuitable for thepurpose at hand, it can be readily converted to another, more suitableform. For pharmaceutical purposes, acid-addition salts of the compoundsof Formula I and Formula II with relatively non-toxic, pharmaceuticallyacceptable acid, for example hydrochloric acid, lactic acid, tartaricacid, and the like, are of course employed.

The mono esters of Formulas I and II wherein Y¹ is hydrogen are ofcourse amphoteric, having both free phenol and basic amino groups, andthus form salts with both acids and bases.

The manner and process of making and using the invention, and the bestcontemplated by the inventors of carrying out this invention, will nowbe described so as to enable any person skilled in the art to which itpertains to make and use the same.

The esters of Formula I hereinabove wherein Y² is hydrogen are obtainedin accordance with the invention by reducing an ester ketone of FormulaIII. Similarly, the esters of Formula II hereinabove wherein Y² ishydrogen are obtained by reducing an ester-ketone of Formula IV. As willof course be appreciated, in effecting reduction of these ester-ketonesof Formulas III and IV to the corresponding ester-alcohols, the use ofreducing means resulting in reduction of carboxylic ester groupings mustbe avoided. Ordinarily, it is preferred to effect the desired reductioneither by catalytic hydrogenation in the presence of a noble metalcatalyst such as platinum or palladium, or by employing an alkali metalborohydride and a lower alkanol. In those instances where one or both ofY and Y¹ in the ester-ketones of Formulas III and IV contain an olefinicdouble bond, and it is desired to retain this unsaturation in thereduction product (Formula I or II wherein Y² is hydrogen), theborohydride method is used since, as is well known, catalytichydrogenation effects reduction of such double bonds.

The catalytic hydrogenation process is conveniently carried out in asuitable solvent, for example ethyl alcohol, at 20°-60° C. underpressure, for instance on the order of 20-50 pounds of hydrogen pressureper squaare inch, in the presence of palladium or platinum hydrogenationcatalyst. The hydrogenation is continued until the theoretical amount ofhydrogen is absorbed as calculated in conventional fashion from drop inhydrogen pressure. A hydrogenation time of 4 hours or less is generallysatisfactory. After removal of the catalyst, the isolation of theester-alcohol product is effected in conventional manner, as byevaporation of some or all of the solvent from the reaction mixture,collecting the precipitated crude ester-alcohol, and purifying it byrecrystallization from a suitable solvent.

In some instances, when applied to the ester ketones of Formula IV, thecatalytic hydrogenation method may result in the production of anundesired byproduct by reduction of the 3-(Y-O-CH₂ -) group to a 3-(CH₃-) group. In such cases, for best results it may be preferable to employthe borohydride reduction method.

The ester-ketones of Formulas III and IV used as starting materials inthe reduction process described hereinabove are obtained by mono- ordi-esterifying the corresponding known and readily available3,4-dihydroxyphenyl (R-NH-)(R')-methyl ketones of Formula V and3-hydroxymethyl-4-hydroxyphenyl (R-NH-)(R')methyl ketones of Formula VI,respectively. .[.When R is hydrogen, methyl, or ethyl, to preventundesired N-acylation it is advantageous to N-benzylate (N,N-dibenzylatewhen R is hydrogen) the ketone of Formula V before the esterification iscarried out. These protective N-benzyl groups can of course be readilyremoved by catalytic hydrogenation either at the ester ketone stage orat the ester alcohol stage (final product), as desired..].

For the production of the mono-ester ketones of Formula III wherein Y¹is hydrogen, the starting 3,4-dihydroxyphenyl (R-NH-)(R'-)methyl ketone(Formula V) is treated with one molecular equivalent of an acidanhydride or an acid halide of the appropriate carboxylic acid (Y-OHwherein Y has the significance indicated hereinabove), optionally butpreferably in the presence of an acid-absorbing medium, in any suitablemanner for the acylation of phenolic hydroxyl. In one preferredprocedure, the 3,4-dihydroxyphenyl (R-NH-)(R')methyl ketone (Formula V)is treated with two molecular equivalents of an alkali metal loweralkoxide, for instance sodium methoxide, and the resulting alkali metalphenolate is treated with one molecular equivalent of the appropriateacid halide, Y-halogen wherein Y has the same significance indicatedhereinabove, for instance the acid chloride, Y-Cl. The 4-hydroxy groupin the starting 3,4-dihydroxyphenyl (R-NH-)(R')methyl ketone (Formula V)is more readily acylated than the 3-hydroxyl group, and thus themonoacylation produces the desired 3-hydroxyphenyl-4-acyloxyphenyl(R-NH-)(R')methyl ketone (Formula III wherein Y' is hydrogen).

The mono-ester ketones of Formula IV wherein Y¹ is hydrogen are readilyobtained either by selectively esterifying the alcoholic hydroxylwithout esterifying the phenolic hydroxyl or by selectivelymono-deacylating the diester (obtained as indicated hereinbelow) toconvert the 4-acyloxy group to 4-hydroxyl while leaving the3-acyloxymethyl group intact. The selective esterification isconveniently effected by reacting the ketone of Formula VI with one moleequivalent of a mixed anhydride of the formula Y¹ --CO--O--CO--CF₃,wherein Y¹ has the same significance indicated hereinabove, intrifluoroacetic acid. If desired, it is satisfactory and ordinarily moreconvenient to form the mixed anhydride in situ by mixing the appropriateacid chloride, Y¹ --Cl, with trifluoroacetic acid. In the selectivemono-deacylation method, a diester of Formula IV wherein Y¹ is an acylgroup is treated at room temperature with a relatively weak organic basesuch as benzylamine or 2-phenylcyclopropylamine inN,N-dimethylformamide, dimethylsulfoxide, or similar solvent, wherebythere is obtained the desired mono-ester of Formula IV where Y¹ ishydrogen.

The di-ester ketones of Formula III and IV wherein both of Y and Y' areacyl groups are obtained by acylating the3-hydroxy-4-acyloxyphenyl(R-NH-)(R')methyl ketones (Formula III whereinY¹ is hydrogen) and the 3-(acyloxymethyl)-4-hydroxyphenyl(R-NH-)(R')methyl ketones (Formula IV wherein Y¹ is hydrogen, obtainedas above-described, with one molecular equivalent of an acid anhydrideor an acid halide of the appropriate carboxylic acid (Y--OH) which iseither different from or the same as the acylating agent used in thefirst acylation step. As will be appreciated, when it is desired that Yand Y¹ in the di-ester ketone (Formula III and Formula IV) be identical,it is generally more convenient to prepare these products by introducingboth acyl groups in a single procedure by employing two molecularequivalents of the acylating agent, and thereby proceed directly to thedesired diester ketone without isolation of the intermediately-formedmono-ester ketone. When the alkali metal phenolate method is employed,the starting 3,4-dihydroxyphenyl (R-NH-)(R')-methyl ketones of Formula Vare of course reacted with two molecular equivalents of alkali metallower alkoxide so as to replace both of the phenolic hydrogens with thealkali metal, whereas the 3-hydroxymethyl-4-hydroxyphenyl(R-NH-)(R')methyl ketones of formula VI require use of only onemolecular equivalent of alkali metal alkoxide.

In the preparation of the di-ester ketones of Formula IV, a procedurealternative to the one above-described comprises forming a3-(acyloxymethyl)-4-acyloxy-alpha-(R')-acetophenone, brominating toproduce a3-(acyloxymethyl)-4-acyloxy-alpha-(R')-alpha-bromoacetophenone, andaminating this product at very low temperature, preferably in the range-20° C. to -60° C. with the appropriate aminating agent having theformula R-NH₂ wherein R has the same significance indicated hereinabove.For the preparation of mono-esters of Formula IV wherein Y¹ is hydrogen,this method is readily modified by selective removal of the 4-acyloxygroup by treating the3-(acyloxymethyl)-4-acyloxy-alpha-(R')-acetophenone with benzylamine, orthe like weak organic base, in N,N-dimethylformamide, dimethylsulfoxide, or similar solvent, and subjecting the resulting3-acyloxymethyl-4-hydroxy-alpha-(R')-acetophenone to the bromination andamination steps as indicated. Alternatively, if it is desired to obtaina mixed di-ester of Formula IV wherein Y and Y' are different acylgroups, the 3-acyloxymethyl-4-hydroxy-alpha-(R')-acetophenone isappropriately acylated to yield a3-acyloxymethyl-4-acyloxy-alpha-(R')-acetophenone wherein the acylgroups are different and thereafter subjecting this product to theindicated bromination and amination procedures.

The preparation of the esters of Formula I and Formula II wherein Y² isacyl are obtained generally by esterification of the correspondingester-alcohols of Formula I and Formula II wherein Y² is hydrogen. Thisesterification is conveniently effected by treatment of anacid(strong)-addition salt of the ester-alcohol, for instance ahydrohalide or methanesulfonate salt, with the appropriate acid halideof formula Y-halogen, preferably the acid halide, Y-Cl, wherein Y hasthe same significance indicated hereinabove.

The esters of Formula II wherein Y¹ is hydrogen and Y² is acyl arealternatively obtained by preferential hydrolysis of the triesters ofFormula II wherein Y Y¹, and Y² are each acyl to convert the 4-acyloxygroup to 4-hydroxy while leaving the other two ester groups intact.

The esters of this invention, having as above-indicated in free baseform the Formulas I and II, when administered orally, intratracheally,intraduodenally, or intravenously to warm-blooded mammals are useful forproducing sympathomimetic effects of substantially longer duration thanthe corresponding unesterified sympathomimetic agents.

Generally speaking, the di-esters of Formula I and Formula II (whereinY¹ is acyl) have longer duration of sympathomimetic action than thecorresponding mono-esters of Formula I and Formula II (wherein Y¹ ishydrogen). Particularly preferred embodiments of this invention are theesters of the sympathomimetic agents, for instance3,4-dihydroxy-alpha-(isopropylaminomethyl)benzyl alcohol and especially3,4-dihydroxy-alpha-(tert-butylaminomethyl)benzyl alcohol, which haveuseful bronchodilator action. These particularly preferred esters, whichare those having Formula I wherein R' is hydrogen and R is isopropyl ortert-butyl, not only have longer duration of bronchodilator action thanthe corresponding unesterified bronchodilator agents, when administeredorally, intratracheally, intraduodenally, or intravenously towarm-blooded mammals but also advantageously produce lowercardiovascular effects than the corresponding unesterified compounds. Inthis group of preferred esters the diesters especially those wherein oneof Y and Y¹ is benzoyl or substituted benzoyl and the other is benzoyl,substituted benzoyl, or alkanoyl, afford special advantages.

In carrying out the method aspect of this invention, i.e. the method ofproducing sympathomimetic effects of long duration in warm-bloodedmammals which comprise administering to said mammal an effective amountof an ester having in the free base form Formula I or Formula IIhereinabove, the said esters are orally administered in the same manneras the known corresponding unesterified sympathomimetic. Thus, they canbe used with any of the pharmaceutically acceptable carriersconventionally employed for oral or parenteral administration of suchagents. Ordinarily, they are combined with conventional pharmaceuticalsolid or liquid diluents and carriers in tablets, capsules, syrups,emulsions, solutions, suspensions or the like. The formulations maycontain any of the usual excipients was water, lactose, starch,magnesium stearate, talc, gelatin, calcium carbonate, gums, and thelike. An especially preferred method for administering these esters(Formula I and Formula II) is in the form of an aerosol inhalentpreparation, for example of the general type conventionally used inaerosol therapy, as in the treatment of bronchospasms, wherein asympathomimetic agent with effective bronchodilator activity isincorporated with suitable carriers and an inert propellent in anebulizing unit. A typical formulation of the aerosol type contains, byweight: 0.25 percent of the ester (Formula I or Formula II) or asuitable pharmaceutically-acceptable salt thereof, 39.75 percent ofU.S.P. ethanol, 48 percent of dichlorotetrafluoroethane, and 12.00percent of dichlorodifluoromethane.

The individual unit dosage can be varied as desired. For general use itis preferred to incorporate, in a solid vehicle, table or capsule, about0.1 to 100 mg. of the ester (Formula I or Formula II); or in a liquidvehicle, about 0.1 to 100 mg. of the ester (Formula I or Formula II) perteaspoonful or, in an aerosol, 0.02 to 2 mg. per actuation. Theeffective oral dose for producing bronchodilation is in the approximaterange 0.002-2.0 mg./kg.

This invention is illustrated by the following examples without,however, being limited thereto.

EXAMPLE 1

A. A mixture of 25 g. of 3,4-dihydroxyphenyl N-tert-butylaminomethylketone hydrochloride, 150 ml. of butyric acid saturated with hydrogenchloride, and 150 ml. of butyryl chloride was stirred on a steam bathuntil a clear solution was obtained (in about 6 hours) and the solutionwas heated on the steam bath for one hour. Approximately 50 ml. ofsolvent was distilled under reduced pressure from the reaction mixturewhich was then cooled. The mixture was filtered to collect a crystallinesolid product which was washed well with diethyl ether and sucked dryunder a rubber dam overnight. There was thus obtained 31 g. of3,4-bis(-butyryloxy)phenyl N-tert-butylaminomethyl ketone hydrochlorideas a white crystalline solid which melted at 212°-215° C.(dec.)(uncorr.).

B. A mixture of 30 g. of 3,4-bis(butyryloxy)phenylN-tert-butylaminomethyl ketone hydrochloride, 200 ml. of 90 percentethyl alcohol, and 2 g. of 10 percent palladium-on-charcoalhydrogenation catalyst was hydrogenated for 2 hours at 50° C. under aninitial hydrogen pressure of 50 pounds per square inch. Thehydrogenation mixture was filtered to remove the catalyst. The solventwas evaporated from the filtrate under reduced pressure and theresulting residue was taken up in 50 ml. of isopropyl alcohol, allowedto stand overnight at 5° C., and filtered to remove 3 g. of solid. Thefiltrate was evaporated under reduced pressure, the residue thusobtained was dissolved in 50 ml. of isopropyl acetate, and this solutionwas filtered to remove a small amount of insoluble solid. When thefiltrate was diluted with anhydrous diethyl ether, a solid separatedfrom solution. This solid was collected on a filter. There was thusobtained 20 g. of crude3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride. This salt was dissolved in water and then ammoniumhydroxide was added, resulting in precipitation of the free base,3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol. Thisprecipitate was collected on a filter and washed well first with waterand then with n-hexane. This base, which melted at 97°-99° C. (uncorr.),was dissolved in isopropyl alcohol and this solution was concentratedunder reduced pressure. The resulting residue was dissolved in 30 ml. ofisopropyl acetate and there was added ethereal hydrogen chloridesolution in an amount affording a slight excess of the required amountof hydrogen chloride for conversion of the base to the hydrochloride.The mixture was cooled and the inside of the container was scratched toinduce crystallization. The mixture was diluted with 100 ml. of diethylether and the solid precipitate was collected on a filter and washedwith anhydrous diethyl ether and dried at 70° C. There was thus obtained11 g. of 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride as a white crystalline solid which melted at 136°-138° C.(uncorr.). This salt was soluble in water to the extent of at least 20percent. The pH of a 1 percent aqueous solution of this salt was 6.0;and a precipitate formed when the pH of this solution was raised to 7.0by addition of N/10 sodium hydroxide solution.

EXAMPLE 2

A. To a mixture of 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethylketone hydrochloride in 200 ml. of N,N-dimethylformamide under anatmosphere of nitrogen there was added 17 g. of sodium methoxide. Bydistillation under reduced pressure, 50 ml. of liquid was removed andthe mixture was then cooled and under an atmosphere of nitrogen 25 g. ofisobutyryl chloride was added rapidly at 5°-25° C. The reaction mixturewas stirred at 25° C. for 1 hour and then was warmed to 70° C. and thesolvent was removed by distillation. The resulting residue was slurriedin 400 ml. of diethyl ether, and the slurry was filtered to remove about10 g. of insoluble solid. The ethereal layer in the filtrate wasseparated, washed with dilute aqueous sodium hydroxide solution and thenwith water. There was thus obtained an ether solution of3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone. To thissolution there was added a solution obtained by adding 4 ml. ofhydrochloric acid to 25 ml. of water, and the resulting mixture wasshaken. The crystalline solid which formed was collected on a filter anddried at 70° C. There was thus obtained 8.5 g. of3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone hydrochlorideas a white crystalline powder which melted at 221°-223° C.(dec.)(uncorr.).

B. By catalytic hydrogenation of 8.5 g. of 3,4-bis(isobutyryloxy)phenyltert-butylaminomethyl ketone hydrochloride in 200 ml. of 95 percentethyl alcohol in the presence of 2 g. of 10 percentpalladium-on-charcoal catalyst there was obtained 5.0 g. of3,4-bis(isobutyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride as a white crystalline powder which melted at 190° C.(uncorr.).

EXAMPLE 3

A. A mixture of 25 g. of 3,4-dihydroxyphenyl tert-butylaminomethylketone hydrochloride, 100 g. of isovaleryl chloride, and 100 g. ofisovaleric acid was stirred on a steam bath for 72 hours. The reactionmixture was allowed to stand overnight at room temperature(approximately 25° C.) and then was heated and filtered while hot toremove 18 g. of solid. The filtrate was evaporated to dryness underreduced pressure and the resulting residue was crystallized fromisopropyl acetate containing a small amount of acetic acid. There wasthus obtained 11.2 g. of 3,4-bis(isovaleryloxy)phenyltert-butylaminomethyl ketone hydrochloride as a white crystalline solidwhich melted at 220°-222° C. (uncorr.). After recrystallization of asample of this compound from isopropyl alcohol the melting point was224°-225° C.

B. By catalytic hydrogenation of 11.2 g. of 3,4-bis(isovaleryloxy)phenyltert-butylaminomethyl ketone hydrochloride in 250 ml. of 95 percentethyl alcohol in the presence of 2 g. of 10 percentpalladium-on-charcoal catalyst there was obtained 3.6 g. of3,4-bis(isovaleryloxy)-alpha-(tert-butylaminomethyl)-benzyl alcoholhydrochloride as a white crystalline powder which melted at 173° C.(uncorr.). This salt was soluble in water at 25° C. to the extent of atleast 20 percent. The pH of a 1 percent aqueous solution was 5.4; andwhen the pH of this solution was adjusted to 7.0 by addition of N/10sodium hydroxide solution, a precipitate formed.

EXAMPLE 4

A. A mixture of 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethylketone hydrochloride, 50 g. of 2-methylbutanoyl chloride, 100 g. of2-methylbutanoic acid, and 0.5 g. of aluminum chloride was heated withvigorous stirring at 120° C. for 1 hour. Then, since evolution ofhydrogen chloride from the reaction mixture had slowed considerably, themixture was heated at 145° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure, the resulting residue was slurriedin 300 ml. of boiling acetone, and the slurry was filtered. The solidthus collected, which was 3,4-bis(2-methylbutanoyloxy)-phenyltert-butylaminomethyl ketone hydrochloride, weighed 30 g. and melted at218°-221° C. (uncorr.).

B. By catalytic hydrogenation of 29.5 g. of3,4-bis(2-methylbutanoyloxy)phenyl tert-butylaminomethyl ketonehydrochloride in 200 ml. of 95 percent ethyl alcohol in the presence of2 g. of 10 percent palladium-on-charcoal catalyst there was obtained 26g. of 3,4-bis(2-methylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride as a white crystalline powder which melted at163°-165° C. (uncorr.). The solubility of this salt in water at 25° C.was at least 5 percent.

EXAMPLE 5

A. Proceeding in a manner similar to that described in part A of Example2 above, 17 g. of sodium methoxide was interacted with 26 g. of3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200ml. of N,N-dimethylformamide and the resulting sodium phenolate salt wasinteracted with 24 g. of pivalyl chloride (alternatively designated astrimethylacetyl chloride or 2,2-dimethylpropanoyl chloride). From thisacylation reaction there was obtained 3,4-bis(pivalyloxy)phenyltert-butylaminomethyl ketone which was treated with hydrochloric acid toyield 11.5 g. of 3,4-bis(pivalyloxy)phenyl tert-butylaminomethyl ketonehydrochloride as a white crystalline solid which melted at 243°-244° C.(dec.)(uncorr.). This salt was soluble in water at 25° C. to the extentof at least 1 percent.

B. By catalytic hydrogenation of 11.7 g. of 3,4-bis-(pivalyloxy)phenyltert-butylaminomethyl ketone hydrochloride in 200 ml. of 95 percentethyl alcohol in the presence of 2. g. of 10 percentpalladium-on-charcoal catalyst there was obtained 8.0 g. of3,4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride as a white crystalline powder which melted at 249° C.(uncorr.). This salt was soluble in water at 25° C. to the extent of atleast 5 percent.

EXAMPLE 6

A. Proceeding in a manner similar to that described in Example 1A above,10.4 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketonehydrochloride, 24 ml. of 3-methylpentanoyl chloride, and 40 ml. of3-methylpentanoic acid were interacted to yield 4.5 g. of3,4-bis(3-methylpentanoyloxy)phenyl tert-butylaminomethyl ketonehydrochloride as a white crystalline solid which melted at 139°-140° C.(uncorr.).

B. By catalytic hydrogenation of 4.5 g. of3,4-bis(3-methylpentanoyloxy)phenyl tert-butylaminomethyl ketonehydrochloride in 100 ml. of anhydrous ethyl alcohol in the presence of0.5 g. of 10 percent palladium-on-charcoal catalyst there was obtained2.7 g. of3,4-bis(3-methylpentanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride as a white crystalline solid which melted at139°-140° C. (uncorr.). This salt was soluble in water at 25° C. to theextent of at least 5 percent.

EXAMPLE 7

A. Proceeding in a manner similar to that described in Example 2A above,26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloridewas interacted with 17 g. of sodium methoxide and the resulting sodiumphenolate salt was interacted with 25 g. of 3,3-dimethylbutanoylchloride to yield 7.0 g. of 3,4-bis(3,3-dimethylbutanoyloxy)phenyltert-butylaminomethyl ketone hydrochloride as a white crystalline solidwhich melted at 225°-228° C. (dec.)(uncorr.).

B. By catalytic hydrogenation of 7.0 g. of3,4-bis(3,3-dimethylbutanoyloxy)phenyl tert-butylaminomethyl ketonehydrochloride in 200 ml. of 95 percent ethyl alcohol in the presence of2 g. of 10 percent palladium-on-charcoal catalyst there was obtained 6.0g. of3,4-bis(3,3-dimethylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride as a white crystalline powder which melted at 226°C. (uncorr.). This salt was soluble in water at 25° C. to the extent ofat least 1 percent.

EXAMPLE 8

A. Proceeding in a manner similar to that described in Example 2A above,26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloridewas interacted with 18 g. of sodium methoxide, and the resulting sodiumphenolate salt was interacted with 30 ml. of 2,2-dimethypentanoylchloride to yield 17 g. of 3,4-bis(2,2-dimethylpentanoyloxy)phenyltert-butylaminomethyl ketone hydrochloride as a white crystalline solidwhich melted at 183°-185° C. (uncorr.).

B. By catalytic hydrogenation of 15 g. of3,4-bis(2,2-dimethylpentanoyloxy)phenyl tert-butylaminomethyl ketonehydrochloride in 200 ml. of 95 percent ethyl alcohol in the presence of2 g. of 10 percent palladium-on-charcoal catalyst there was obtained3,4-bis(2,2-dimethylpentanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride which by treatment with an excess of 10 percentammonium hydroxide was converted to the free base (11 g.). This base wasconverted to its methanesulfonic acid salt (10 g.), a white crystallinepowder which melted at 107°-109° C. (uncorr.). The methanesulfonate wassoluble in water at 25° C. to the extent of at least 5 percent.

EXAMPLE 9

Following the procedure described above in Example 2A but using decanoylchloride instead of isobutyryl chloride there is obtained3,4-bis(decanoyloxy)-phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt as a white crystalline solid which decomposed slowlyabove 235° C. (uncorr.). When this hydrochloride was catalyticallyhydrogenated, using the procedure described above in Example 2B, therewas obtained 3,4-bis(decanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride which was converted to the corresponding freebase, a crystalline white solid, m.p. 73°-74° C. (uncorr.), and thisbase was converted to the methanesulfonate salt, a crystalline whitesolid, m.p. 45°-48° C. (uncorr.).

EXAMPLE 10

Following the procedure described above in Example 2A but usingtetradecanoyl chloride instead of isobutyryl chloride there is obtained3,4-bis(tetradecanoyloxy)phenyl tert-butylaminomethyl ketone, and byinteraction of this base with methanesulfonic acid there is obtained themethanesulfonate salt. When this methanesulfonate is catalyticallyhydrogenated, using the procedure described above in Example 2B, thereis obtained3,4-bis(tetradecanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate.

EXAMPLE 11

Following the procedure described above in Example 2A but usingoctadecanoyl chloride instead of isobutyryl chloride there is obtained3,4-bis(octadecanoyloxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt as a white crystalline solid, m.p. 180°-185° C.(uncorr.). When 14 g. of this hydrochloride was catalyticallyhydrogenated, using the procedure described above in Example 2B, therewas obtained3,4-bis(octadecanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride as a white solid which melted at 75°-78° C. (uncorr.).This hydrochloride was converted to the base by treatment with ammoniumhydroxide, and the base was extracted with diethyl ether. The etherealsolution thus obtained was dried over anhydrous calcium sulfate and thentreated with 1.5 g. of methanesulfonic acid to yield 6.3 g. of3,4-bis-(octadecanoyloxy)-alpha-(tert-buylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 105°-108°C. (uncorr.).

EXAMPLE 12

Following the procedure described above in Example 2A but usingdocosanoyl chloride instead of isobutyryl chloride there is obtained3,4-bis(docosanoyloxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with methanesulfonic acid there is obtained themethanesulfonate salt. When this methanesulfonate is catalyticallyhydrogenated, using the procedure described above in Example 2B, thereis obtained 3,4-bis(docosanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate.

EXAMPLE 13

A. A mixture of 5.2 g. of 3,4-dihydroxy tert-butylaminomethyl ketonehydrochloride, 10 ml. of 1-methylcyclopropanecarbonyl chloride, and 20ml. of 1-methylcyclopropanecarboxylic acid was stirred at 120° C. underslight pressure. After evolution of hydrogen chloride had slowedconsiderably, the temperature of the reaction mixture was raised to 140°C. for 30 minutes. Approximately 10 ml. of solvent was distilled fromthe mixture and the residue, which contained a crystalline solid, wasmixed with anhydrous diethyl ether and filtered. The solid thuscollected, which weighed 7.5 g., was slurried in a waterdiethyl ethermixture and the slurry was made basic by addition of ammonium hydroxide.The ether layer was separated, washed with dilute sodium hydroxidesolution and then with water, and was shaken with a solution prepared bydiluting 3 ml. of concentrated hydrochloric acid to 30 ml. with water.The solid which precipitated was collected on a filter, washed withdiethyl ether, and dried at 70° C. to yield 6.5 g. of3,4-bis-(1-methylcyclopropanecarbonyloxy)phenyl tert-butylaminomethylketone hydrochloride as a white crystalline solid which melted at253°-255° C. (dec.)(uncorr.).

B. By catalytic hydrogenation of 6.1 g. of3,4-bis(1-methylcyclopropanecarbonyloxy)phenyl tert-butylaminomethylketone hydrochloride in 200 ml. of 90 percent ethyl alcohol in thepresence of 2 g. of 10 percent palladium-on-charcoal catalyst there wasobtained 2.6 g. of3,4-bis(1-methylcyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride as a white crystalline powder which melted at210°-212° C. (uncorr.).

EXAMPLE 14

When cyclopropanecarbonyl chloride and cyclopropanecarboxylic acid aresubstituted for the 1-methylcyclopropanecarbonyl chloride and1-methylcyclopropanecarboxylic acid, respectively, in the proceduredescribed in Example 13A above, the acylation product obtained is3,4-bis(cyclopropanecarbonyloxy)phenyl tert-butylaminomethyl ketonehydrochloride; and when this product is catalytically hydrogenated usingthe procedure described in Example 13B above, there is obtained3,4-bis(cyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 15

A. Under an atmosphere of nitrogen, 17.0 g. of sodium methoxide wasadded to a solution of 26.0 g. of 3,4-dihydroxyphenyltert-butylaminomethyl ketone hydrochloride in 200 ml. ofN,N-dimethylformamide. During this addition the temperature of themixture rose to 45° C. The mixture was cooled to 0° C. and under anatmosphere of nitrogen 29.1 g. of cyclohexanecarbonyl chloride was addeddropwise with stirring at 0°-3° C. The reaction mixture was stirred for1 hour at room temperature (about 25° C.) and then was poured into amixture of ice water and diethyl ether. The ether layer was separated,washed successively with water, dilute aqueous sodium hydroxidesolution, and water, and dried over anhydrous calcium sulfate. Etherealhydrogen chloride solution was added to the dry ether solution and thesolid which precipitated was collected on a filter. The product thuscollected was recrystallized from 200 ml. of isopropyl alcohol to yield11 g. of 3,4-bis(cyclohexanecarbonyloxy)phenyl tert-butylaminomethylketone hydrochloride as a white crystalline solid which melted at204°-210° C. (dec.) (uncorr.).

B. By catalytic hydrogenation of 10.6 g. of3,4-bis(cyclohexanecarbonyloxy)phenyl tert-butylaminomethyl ketonehydrochloride in 100 ml. of anhydrous ethyl alcohol in the presence of1.0 g. of 10 percent palladium-on-charcoal catalyst there was obtained8.2 g. of3,4-bis(cyclohexanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride as a white crystalline solid which melted at212°-213° C. (uncorr.). The solubility of this salt in each of water andpolyethyleneglycol at 25° C. was less than 0.1 percent. When a 1 percentsolution of this salt in dimethyl sulfoxide was diluted with threevolumes of water, no precipitate formed.

EXAMPLE 16

When cyclobutanecarbonyl chloride is substituted for thecyclohexanecarbonyl chloride in the procedure described in Example 15Aabove, the acylation product obtained is3,4-bis-(cyclobutanecarbonyloxy)phenyl tert-butylaminomethyl ketone; andwhen this product is catalytically hydrogenated using the proceduredescribed in Example 15B above there is obtained3,4-bis(cyclobutanecarbonyloxy)-alpha-(tert-butylaminomethyl)-benzylalcohol.

EXAMPLE 17

When cyclopentanecarbonyl chloride is substituted for thecyclohexanecarbonyl chloride in the procedure described in Example 15Aabove, the acylation product obtained is3,4-bis(cyclopentanecarbonyloxy)phenyl tert-butylaminomethyl ketone; andwhen this product is catalytically hydrogenated using the proceduredescribed in Example 15B above, there is obtained3,4-bis(cyclopentanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 18

When cycloheptanecarbonyl chloride is substituted for thecyclohexanecarbonyl chloride in the procedure described in Example 15Aabove, the acylation product obtained is3,4-bis(cycloheptanecarbonyloxy)phenyl tert-butylaminomethyl ketone; andwhen this product is catalytically hydrogenated using the proceduredescribed in Example 15B above, there is obtained3,4-bis(cycloheptanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 19

When 2-hexylcyclopropanecarbonyl chloride is substituted for thecyclohexanecarbonyl chloride in the procedure described in Example 15Aabove, the acylation product obtained is3,4-bis(2-hexylcyclopropanecarbonyloxy)phenyl tert-butylaminomethylketone; and when this product is catalytically hydrogenated using theprocedure described in Example 15B above, there is obtained3,4-bis(2-hexylcyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 20

When 1-methyl-3-isopropylcyclopentanecarbonyl chloride is substitutedfor the cyclohexanecarbonyl chloride in the procedure described inExample 15A above, the acylation product obtained is2,4-bis(1-methyl-3-isopropylcyclopentanecarbonyloxy)phenyltert-butylaminomethyl ketone; and when this product is catalyticallyhydrogenated using the procedure described in Example 15B above, thereis obtained3,4-bis(1-methyl-3-isopropylcyclopentanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 21

When 1,3-dimethylcyclobutanecarbonyl chloride is substituted for thecyclohexanecarbonyl chloride in the procedure described in Example 15Aabove, the acylation product obtained is3,4-bis(1,3-dimethylbutanecarbonyloxy)phenyl tert-butylaminomethylketone; and when this product is catalytically hydrogenated using theprocedure described in Example 15B above, there is obtained3,4-bis(1,3-dimethylcyclobutanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 22

When 2-amylcyclopropaneacetyl chloride is substituted for thecyclohexanecarbonyl chloride in the procedure described in Example 15Aabove, the acylation product obtained is3,4-bis(2-amylcyclopropaneacetoxy)phenyl tert-butylaminomethyl ketone;and when this product is catalytically hydrogenated using the proceduredescribed in Example 15B above, there is obtained3,4-bis(2-amylcyclopropaneacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 23

When 2,2-dimethyl-3-ethylcyclobutaneacetyl chloride is substituted forthe cyclohexanecarbonyl chloride in the procedure described in Example15A above, the acylation product obtained is3,4-bis(2,2-dimethyl-3-ethylcyclobutaneacetoxy)phenyltert-butylaminomethyl ketone; and when this product is catalyticallyhydrogenated using the procedure described in Example 15B above, thereis obtained3,4-bis(2,2-dimethyl-3-ethylcyclobutaneacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 24

Following the procedure described above in Example 15A but usingcyclohexaneacetyl chloride instead of cyclohexanecarbonyl chloride theacylation product obtained is 3,4-bis(cyclohexaneacetoxy)phenyltert-butylaminomethyl ketone; and when this product is catalyticallyhydrogenated, using the procedure described above in Example 15B, thereis obtained3,4-bis(cyclohexaneacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.

EXAMPLE 25

When 4-methylcycloheptaneacetyl chloride is substituted for thecyclohexanecarbonyl chloride in the procedure described in Example 15Aabove, the acylation product obtained is3,4-bis(4-methylcycloheptaneacetoxy)phenyl tert-butylaminomethyl ketone;and when this product is catalytically hydrogenated using the proceduredescribed in Example 15B above, there is obtained3,4-bis(4-methylcycloheptaneacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 26

When 2-isobutylcyclopropanepropionyl chloride is substituted for thecyclohexanecarbonyl chloride in the procedure described in Example 15A,above, the acylation product obtained is3,4-bis(2-isobutylcyclopropanepropionyloxy)phenyl tert-butylaminomethylketone; and when this product is catalytically hydrogenated using theprocedure described in Example 15B above, there is obtained3,4-bis(2-isobutylcyclopropanepropionyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 27

Following the procedure described above in Example 15A but usingcycloheptanepropionyl chloride instead of cyclohexanecarbonyl chloridethe acylation product obtained is3,4-bis(cycloheptanepropionyloxy)phenyl tert-butylaminomethyl ketone;and when this product is catalytically hydrogenated, using the proceduredescribed above in Example 15B, there is obtained3,4-bis(cycloheptanepropionyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 28

Following the procedure described above in Example 15A but usingalpha-methylcyclopropaneacetyl chloride instead of cyclohexanecarbonylchloride the acylation product obtained is3,4-bis(alpha-methylcyclopropaneacetoxy)phenyl tert-butylaminomethylketone; and when this product is catalytically hydrogenated, using theprocedure described above in Example 15B, there is obtained3,4-bis(alphamethylcyclopropaneacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

EXAMPLE 29

A. To 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketonehydrochloride in 200 ml. of dioxane there was added rapidly 20 g. ofpotassium hydroxide in 50 ml. of methanol. One-half of the solvent wasdistilled from the resulting mixture under reduced pressure and then 29g. of benzoyl chloride was dripped in at 5°-10° C. during a period of 30minutes. The reaction mixture was stirred for another half-hour at 10°C., after which the solvent was distilled off under reduced pressure.The residue thus obtained was slurried with a mixture of 100 ml. and 400ml. of diethyl ether, and the slurry was filtered to remove 12 g. ofinsoluble solid. The ether layer in the filtrate was separated, washedwith water, dilute aqueous sodium hydroxide solution, and water, andthen was shaken with a solution of 7 ml. of concentrated hydrochloricacid in 50 ml. of water. The mixture was cooled in ice and theprecipitate which formed was collected on a filter and washed with a fewml. of water and then with diethyl ether, and dried at 70° C. There wasthus obtained 11.0 g. of 3,4-bis(benzoyloxy)phenyl tert-butylaminomethylketone hydrochloride as a white crystalline solid which melted at215°-218° C. (dec.) (uncorr.).

B. By catalytic hydrogenation of 11 g. of 3,4-bis(benzoyloxy)phenyltert-butylaminomethyl ketone hydrochloride in 200 ml. of anhydrous ethylalcohol in the presence of 1.0 g. of 10 percent palladium-on-charcoalcatalyst there was obtained 6.0 g. of3,4-bis(benzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride which crystallized from a diethyl etheraceticacid-isopropyl acetate mixture as a white solid which melted at214°-216° C. (uncorr.). The solubility of this salt in each ofdimethylsulfoxide and glycerol formal at 25° C. was 1 percent or more;and when a 1 percent solution of this salt in each of these solvents wasdiluted with three volumes of water, no precipitate formed in eitherinstance.

EXAMPLE 30

A. Under an atmosphere of nitrogen, 26 g. of 3,4-dihydroxyphenyltert-butylaminomethyl ketone hydrochloride was mixed with 17 g. ofsodium methoxide in 200 ml. of N,N-dimethylformamide and 50 ml. ofsolvent was distilled off below 40° C. under reduced pressure. Then 31g. of p-toluyl chloride was dripped in at 5°-10° C. The solvent wasdistilled from the reaction mixture under reduced pressure, theresulting residue was slurried in a mixture of water and diethyl ether,and the slurry was filtered to remove 9.5 g. of insoluble solid. Theether layer in the filtrate, which contained 3,4-bis(p-toluyloxy)phenyltert-butylaminomethyl ketone, was separated, washed with water anddilute sodium hydroxide, and then was shaken with a solution obtained bydiluting 4 ml. of concentrated hydrochloric acid with water to a volumeof 30 ml. After the mixture had stood for 1 hour at room temperature,the precipitate which had formed was collected on a filter, washed withdiethyl ether, and recrystallized from isopropyl alcohol. There was thusobtained 14.0 g. of 3,4-bis(p-toluyloxy)phenyl tert-butylaminomethylketone hydrochloride as a white crystalline solid which melted at221°-224° C. (uncorr.). The solubility of this salt in water at 25° C.was less than 0.1 percent.

B. By catalytic hydrogenation of 13.5 g. of 3,4-bis(p-toluyloxy)phenyltert-butylaminomethyl ketone hydrochloride in 220 ml. of anhydrous ethylalcohol at room temperature in the presence of 2.0 g. of 10 percentpalladium-on-charcoal catalyst until one mole equivalent of hydrogen wasabsorbed (about 30 min. required), there was obtained 8.0 g. of crude,3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride as a pulvurulent solid which by treatment with an excessof 10 percent ammonium hydroxide was converted to the free base, whichweighed 4.3 g. and melted at 80°-84° C. This base was converted to itsmethanesulfonic acid salt (4.3 g.), a white crystalline powder whichmelted at 170°-172° C. (uncorr.). The methanesulfonate was soluble indimethyl sulfoxide to the extent of at least 1 percent; and when a 1percent solution of dimethyl sulfoxide was diluted with three volumes ofwater, no precipitate formed.

C. To a solution of 1.1 g. of 3,4-bis(p-toluyloxy)phenyltert-butylaminomethyl ketone methanesulfonate (m.p. 185°-187° C.(uncorr.) obtained by reacting the free base with methanesulfonic acid)in 20 ml. of anhydrous methyl alcohol at 5° C. under an atmosphere ofnitrogen there was added with stirring 100 mg. of dry sodiumborohydride. After 5 minutes the reaction was quenched with aboutfifteen drops of glacial acetic acid to bring the pH of the mixture toapproximately 6. The mixture was evaporated to dryness, diluted with 200ml. of diethyl ether, and washed with 100 ml. of 5 percent aqueoussodium bicarbonate solution, followed by washing successively with waterand water saturated with sodium chloride. The aqueous washes werecombined and extracted with diethyl ether and this extract was combinedwith the ethereal solution, dried over sodium sulfate, and evaporated toyield 1 g. of colorless oil. This oil, which was3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol, wasdiluted with 70 ml. of anhydrous diethyl ether and 0.14 ml. ofmethanesulfonic acid was added. A white precipitate formed on cooling.The mixture was concentrated to a volume of about 25 and filtered. Thewhite crystalline solid thus obtained, which weighted 1.1 g., was3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate, identical with the product described above in part B.The corresponding acetate salt was a white solid, m.p. 110° C.(uncorr.).

EXAMPLE 31

Following the procedure described above in Example 29A but usingp-tert-butylbenzoyl chloride instead of benzoyl chloride there isobtained 3,4-bis(p-tert-butylbenzoyloxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using the procedure described above inExample 29B, there is obtained3,4-bis(p-tert-butylbenzoyloxy)-alpha-(tert-butylaminomethyl)-benzylalcohol hydrochloride.

EXAMPLE 32

Following the procedure described above in Example 29A but using2-methyl-4-ethylbenzoyl chloride instead of benzoyl chloride there isobtained 3,4-bis(2-methyl-4-ethylbenzoyloxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using the procedure described above inExample 29B, there is obtained,3,4-bis(2-methyl-4-ethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 33

A. Proceeding in a manner similar to that described in Example 30Aabove, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketonehydrochloride was reacted with 17 g. of sodium methoxide in 200 ml. ofN,N-dimethylformamide, and the resulting sodium phenolate salt wasinteracted with p-anisoyl chloride to yield 12.3 g. of3,4-bis(p-anisoyloxy)phenyl tert-butylaminomethyl ketone hydrochlorideas a white crystalline solid which melted at 205°-208° C. (uncorr.).

B. By catalytic hydrogenation of 12.0 g. of 3,4-bis(p-anisoyloxy)phenyltert-butylaminomethyl ketone hydrochloride in 300 ml. of anhydrous ethylalcohol in the presence of 2.0 g. of 10 percent palladium-on-charcoalcatalyst there was obtained 6.2 g. of3,4-bis(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride as a white crystalline solid which melted at 165° C.(uncorr.). The solubility of this salt in polyethyleneglycol 200 at 25°C. was less than 1 percent When 1 percent solutions of this salt in eachof dimethyl sulfoxide and glycerol formal were diluted with 3 volumes ofwater, no precipitate formed.

EXAMPLE 34

Following the procedure described above in Example 30A but usingp-ethoxybenzoyl chloride instead of p-toluyl chloride there is obtained3,4-bis(p-ethoxybenzoyloxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 30B, thereis obtained3,4-bis(p-ethoxybenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride.

EXAMPLE 35

Following the procedure described above in Example 30A but usingp-acetamidobenzoyl chloride instead of p-toluyl chloride there isobtained 3,4-bis(p-acetamidobenzoyloxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrobromic acid there isobtained the hydrobromide salt. When this hydrobromide is catalyticallyhydrogenated, using the procedure described above in Example 30B, thereis obtained3,4,5-bis(p-acetamidobenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrobromide.

EXAMPLE 36

When 3,4,5-tributoxybenzoyl chloride is substituted for the p-toluylchloride in the procedure described in Example 30A above, there isobtained 3,4-bis(3,4,5-tributoxybenzoyloxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated using the procedure described in Example 30Babove, there is obtained3,4-bis(3,4,5-tributoxybenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 37

Following the procedure described above in Example 30A but using3,5-dimethoxy-4-ethoxybenzoyl chloride instead of p-toluyl chloridethere is obtained 3,4-bis(3,5-dimethoxy-4-ethoxybenzoyloxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 30B, there is obtained3,4-bis(3,5-dimethoxy-4-ethoxybenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 38

Following the procedure described above in Example 30A but using2-bromo-5-chlorobenzoyl chloride instead of p-toluyl chloride there isobtained 3,4-bis(2-bromo-5-chlorobenzoyloxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using the procedure described above inExample 30B, there is obtained3,4-bis(2-bromo-5-chlorobenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 39

Following the procedure described above in Example 30A but using2,3,4-trichlorobenzoyl chloride instead of p-toluyl chloride there isobtained 3,4-bis(2,3,4-trichlorobenzoyloxy)phenyl tert-butylaminomethylketone; and by interaction of this base with methanesulfonic acid thereis obtained the methanesulfonate salt. When this methanesulfonate iscatalytically hydrogenated, using the procedure described above inExample 30B, there is obtained3,4-bis(2,3,4-trichlorobenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate.

EXAMPLE 40

When 2,3,5-trifluorobenzoyl chloride is substituted for the p-toluylchloride in the procedure described in Example 30A above, the productobtained is 3,4-bis(2,3,5-trifluorobenzoyloxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained by hydrochloride salt. When thishydrochloride is catalytically hydrogenated using the proceduredescribed in Example 30B above, there is obtained3,4-bis(2,3,5-trifluorobenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 41

When 3,5-bis(trifluoromethyl)benzoyl chloride is substituted for thep-toluyl chloride in the procedure described in Example 30A above, theproduct obtained is 3,4-bis[3,5-bis-(trifluoromethyl)benzoyloxy]phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated using the proceduredescribed in Example 30B above, there is obtained3,4-bis[3,5(trifluoromethyl)benzoyloxy]-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 42

Following the procedure described above in Example 30A but using2-ethoxy-5-fluorobenzoyl chloride instead of p-toluyl chloride there isobtained 3,4-bis(2-ethoxy-5-fluorobenzoyloxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 30B, there is obtained3,4-bis(2-ethoxy-5-fluorobenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 43

Following the procedure described above in Example 30A but using2,6-dimethyl-4-propoxybenzoyl chloride instead of p-toluyl chloridethere is obtained 3,4-bis(2,6-dimethyl-4-propoxybenzoyloxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 30B, there is obtained3,4-bis(2,6-dimethyl-4-propoxybenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 44

When 2-chloro-3-methoxy-4-methylbenzoyl chloride is substituted for thep-toluyl chloride in the procedure described in Example 30A above, theproduct obtained is3,4-bis(2-chloro-3-methoxy-4-methylbenzoyloxy)-phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated using the proceduredescribed in Example 30B above, there is obtained3,4-bis(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 45

Following the procedure described above in Example 30A but usingphenylacetyl chloride instead of p-toluyl chloride there is obtained3,4-bis(phenylacetoxy)-phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 30B, thereis obtained 3,4-bis(phenylacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 46

Following the procedure described above in Example 30A but usingp-ethylphenylacetyl chloride instead of p-tolyl chloride there isobtained 3,4-bis(p-ethylphenylacetoxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using the procedure described above inExample 30B, there is obtained3,4-bis(p-ethylphenylacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 47

Following the procedure described above in Example 30A but using2,5-dimethyl-4-methoxyphenylacetyl chloride instead of p-toluyl chloridethere is obtained 3,4-bis(2,5-dimethyl-4-methoxyphenylacetoxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 30B, there is obtained3,4-bis(2,5-dimethyl-4-methoxyphenylacetoxy)alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 48

Following the procedure described above in Example 30A but using2-bromo-4,5-diethoxyphenylacetyl chloride instead of p-toluyl chloridethere is obtained 3,4-bis(2-bromo-4,5-diethoxyphenylacetoxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 30B, there is obtained3,4-bis(2-bromo-4,5-diethoxyphenylacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 49

Following the procedure described above in Example 30A but usingβ-phenylpropionyl chloride instead of p-toluyl chloride there isobtained 3,4-bis(β-phenylpropionyloxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using the procedure described above inExample 30B, there is obtained3,4-bis(β-phenylpropionyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 50

Following the procedure described above in Example 30A but usingβ-(2-bromo-4-methoxyphenyl)propionyl chloride instead of p-toluylchloride there is obtained3,4-bis[β-(2-bromo-4-methoxyphenyl)propionyloxy]phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 30B, there is obtained3,4-bis[β-(2-bromo-4-methoxyphenyl)propionyloxy]-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 51

Following the procedure described above in Example 30A but using2-naphthalenecarbonyl chloride instead of p-toluyl chloride there isobtained 3,4-bis(2-naphthalenecarbonyloxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using the procedure described above inExample 30B, there is obtained3,4-bis(2-naphthalenecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 52

Following the procedure described above in Example 30A but usingphenoxyacetyl chloride instead of p-tolyl chloride there is obtained3,4-bis(phenoxyacetoxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 30B, thereis obtained 3,4-bis(phenoxyacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 53

Following the procedure described above in Example 30A but usingp-diethylaminobenzoyl chloride instead of p-toluyl chloride there isobtained 3,4-bis(p-diethylaminobenzoyloxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using the procedure described above inExample 30B, there is obtained3,4-bis-(p-diethylaminobenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 54

Following the procedure described above in Example 30A but usingnicotinoyl chloride instead of p-toluyl chloride there is obtained3,4-bis(nicotinoyloxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 30B, thereis obtained 3,4-bis(nicotinoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 55

Following the procedure described above in Example 2A but usingcrotonoyl chloride instead of isobutyryl chloride there is obtained3,4-bis(crotonoyloxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is reduced with sodiumborohydride, using the procedure described above in Example 30C, thereis obtained 3,4-bis(crotonoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 56

Following the procedure described above in Example 2A but using9-octadecenoyl chloride instead of isobutyryl chloride there is obtained3,4-bis(9-octadecenoyloxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is reduced with sodiumborohydride using the procedure described above in Example 30C, there isobtained 3,4-bis(9-octadecenoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 57

Following the procedure described above in Example 2A but using5,13-docosadienoyl chloride instead of isobutyryl chloride there isobtained 3,4-bis(5,13-docosadienoyloxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride is reduced withsodium borohydride, using the procedure described above in Example 30C,there is obtained3,4-bis(5,13-docosadienoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 58

A. Under an atmosphere of nitrogen, 8.1 g. of sodium methoxide was addedto 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketonehydrochloride in 200 ml. of dimethylformamide and 50 ml. of solvent wasdistilled from the reaction mixture under reduced pressure. Then underan atmosphere of nitrogen 7.8 g. of isovaleryl chloride was dripped inat 20°-25° C. and the reaction mixture was stirred at 25° C. for 1 hour.The solvent was distilled off under reduced pressure and the resultingresidue was taken up in a mixture of 500 ml. of water, 3 ml. of 35percent aqueous sodium hydroxide solution, and 200 ml. of diethyl ether.The ether layer was separated and discarded. The aqueous layer wasacidified with acetic acid and the precipitate which formed wascollected on a filter and washed well with water and n-hexane. There wasthus obtained 12 g. of 3-hydroxy-4-(isovaleryloxy)phenyltert-butylaminomethyl ketone. This base was slurried in 500 ml. ofanhydrous ethyl alcohol and with stirring there was added 68 percentmethanesulfonic acid in an amount (5 ml.) sufficient to produce apersistent acidic reaction in the slurry, which was then stirred until aheavy precipitate formed. The precipitate was collected on a filter andwashed with ethyl alcohol and diethyl ether. There was thus obtained 8.1g. of 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate as a white crystalline solid which melted at 242°-245°C. (dec.)(uncorr.).

B. By catalytic hydrogenation of 8.1 g. of3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate suspended in 250 ml. of 95 percent ethyl alcohol in thepresence of 3.0 g. of 10 percent palladium-on-charcoal catalyst therewas obtained 4.8 g. of3-hydroxy-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 148°-150°C. (uncorr.). The solubility of this salt in water at 25° C. was atleast 5 percent.

EXAMPLE 59

A. Following a procedure similar to that described in Example 58A above,260 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloridewas reacted with 170 g. of sodium methoxide in 2 kg. ofN,N-dimethylformamide, and the resulting sodium phenolate was interactedwith 160 g. of pivalyl chloride to yield 250 g. of3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone. Thehydrochloride of this base was a white crystalline solid which melted at268°-270° C. (dec.)(uncorr.), and the methanesulfonate of the base was awhite crystalline solid which melted at 260°-263° C. (dec.)(uncorr.).

B. By catalytic hydrogenation of 18 g. of 3-hydroxy-4-(pivalyloxy)phenyltert-butylaminomethyl ketone methanesulfonate suspended in one liter of95 percent ethyl alcohol in the presence of 3 g. of 10 percentpalladium-on-charcoal catalyst there was obtained 10.0 g. of3-hydroxy-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 175°-177°C.-(uncorr.).

EXAMPLE 60

By interacting 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketonehydrochloride with 8 ml. of 3,3-dimethylbutanoyl chloride in 35 ml. oftrifluoroacetic acid at room temperature, there was obtained3-hydroxy-4-(3,3-dimethylbutanoyloxy)phenyl tert-butylaminomethyl ketonetrifluoroacetate which was converted to the free base by treatment withammonium hydroxide; and by interaction of this base with methanesulfonicacid there was obtained the methanesulfonate salt, m.p. 240°-245° C.(dec.). When this methanesulfonate was catalytically hydrogenated, usingthe procedure described above in Example 58B, there was obtained3-hydroxy-4-(3,3-dimethylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at176°-178° C. (uncorr.).

EXAMPLE 61

Following the procedure described above in Example 58A but using7,7-dimethyloctanoyl chloride instead of isovaleryl chloride there isobtained 3-hydroxy-4-(7,7-dimethyloctanoyloxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 58B, there is obtained3-hydroxy-4-(7,7-dimethyloctanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 62

When dodecanoyl chloride is substituted for the isovaleryl chloride inthe procedure described in Example 58A above, the product obtained is3-hydroxy-4-(dodecanoyloxy)phenyl tert-butylaminomethyl ketone; byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is catalyticallyhydrogenated using the procedure described in Example 58B above, thereis obtained3-hydroxy-4-(dodecanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride.

EXAMPLE 63

When 2,2,17,17-tetramethyloctadecanoyl chloride is substituted for theisovaleryl chloride in the procedure described in Example 58A above, theproduct obtained is3-hydroxy-4-(2,2,17,17-tetramethyloctadecanoyloxy)phenyltert-butylaminomethyl ketone hydrochloride; and by interaction of thisbase with hydrochloric acid there is obtained the hydrochloride salt.When this hydrochloride is catalytically hydrogenated using theprocedure described in Example 58B above, there is obtained3-hydroxy-4-(2,2,17,17-tetramethyloctadecanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 64

Following the procedure described above in Example 58A but using1-methylcyclopropanecarbonyl chloride instead of isovaleryl chloridethere is obtained 3-hydroxy-4-(1-methylcyclopropanecarbonyloxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 58B, there is obtained3-hydroxy-4-(1-methylcyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 65

Following the procedure described above in Example 58A but usingcycloheptanecarbonyl chloride instead of isovaleryl chloride there isobtained 3-hydroxy-4-(cycloheptanecarbonyloxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 58B, there is obtained3-hydroxy-4-(cycloheptanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 66

Following the procedure described above in Example 58A but usingcyclohexaneacetyl chloride instead of isovaleryl chloride there isobtained 3-hydroxy-4-(cyclohexaneacetoxy)phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using the procedure described above inExample 58B, there is obtained3-hydroxy-4-(cyclohexaneacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 67

Following the procedure described above in Example 58A but usingcyclopentanepropionyl chloride instead of isovaleryl chloride there isobtained 3-hydroxy-4-(cyclopentanepropionyloxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 58B, there is obtained3-hydroxy-4-(cyclopentanepropionyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 68

Following the procedure described above in Example 58A but usingnicotinoyl chloride instead of isovaleryl chloride there is obtained3-hydroxy-4-(nicotinoyloxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 58B, thereis obtained3-hydroxy-4-(nicotinoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride.

EXAMPLE 69

A. Following a procedure similar to that described in Example 58A above,13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloridewas reacted with 8.1 g. of sodium methoxide in 200 ml. ofN,N-dimethylformamide, and the resulting sodium phenolate was interactedwith 8.5 g. of p-toluyl chloride to yield3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone. This basewas converted to the methanesulfonate by treatment, in 200 ml. of warmN,N-dimethylformamide, with methanesulfonic acid. The3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate thus obtained was a white crystalline solid whichweighed 12 g. and melted at 265° C. (dec.)(uncorr.).

B. By catalytic hydrogenation of 12 g. of3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate in 1 liter of 95 percent ethyl alcohol in the presenceof 4 g. of palladium-on-charcoal catalyst there was obtained 7.4 g. of3-hydroxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline powder which melted at 203°-205°C. (uncorr.). The solubility of this salt in water at 25° C. was atleast 5 percent.

EXAMPLE 70

Following the procedure described above in Example 58A but using2,3,4-trichlorobenzoyl chloride instead of isovaleryl chloride there isobtained 3-hydroxy-4-(2,3,4-trichlorobenzoyloxy)phenyltert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 58B, there is obtained3-hydroxy-4-(2,3,4-trichlorobenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 71

A. Following a procedure similar to that described in Example 2A above,when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with isovaleryl chloride there isobtained 3-(isovaleryloxy)-4-(pivalyloxy)phenyl tert-butylaminomethylketone, which reacts with hydrochloric acid to yield the hydrochloridesalt as a white crystalline solid, m.p. 216°-220° C. (uncorr.).

B. By catalytic hydrogenation of 7.7 g. of3-(isovaleryloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketonehydrochloride in 200 ml. of 95 percent ethyl alcohol in the presence of2.0 g. of 10 percent palladium-on-charcoal catalyst there was obtained6.1 g. of3-(isovaleryloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride as a white crystalline solid which melted at202°-204° C. (uncorr.). The solubility of this salt in water at 25° C.was at least 5 percent.

EXAMPLE 72

Following a procedure similar to that described in Example 2A above,when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with pivalyl chloride there is obtained3,4-bis(pivalyloxy)phenyl tert-butylaminomethyl ketone, which reactswith hydrochloric acid to yield the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 2B, there is obtained3,4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride. The ketone intermediate and the alcohol product obtainedin this manner are identical with the ketone and the alcohol describedabove in Example 5A and 5B, respectively.

EXAMPLE 73

Following a procedure similar to that described in Example 2A above,when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with decanoyl chloride there isobtained 3-(decanoyloxy)-4-(pivalyloxy)phenyl tert-butylaminomethylketone which reacts with hydrochloric acid to yield the hydrochloridesalt. When this hydrochloride is catalytically hydrogenated, using theprocedure described above in Example 2B, there is obtained3-(decanoyloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 74

Following a procedure similar to that described in Example 30A above,when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with o-toluyl chloride there isobtained 3-(o-toluyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethylketone which reacts with hydrochloric acid to yield the hydrochloridesalt. When this hydrochloride is catalytically hydrogenated, using theprocedure described above in Example 30B, there is obtained3-(o-toluyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 75

Following a procedure similar to that described in Example 30A above,when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with 3,4,5-trimethoxybenzoyl chloridethere is obtained 3-(3,4,5-trimethoxybenzoyloxy)-4-(pivalyloxy)phenyltert-butylaminomethyl ketone which reacts with hydrochloric acid toyield the hydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 30B, thereis obtained3-(3,4,5-trimethoxybenzoyloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 76

Following a procedure similar to that described in Example 2A above,when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with isovaleryl chloride there isobtained 3-(isovaleryloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethylketone which reacts with hydrochloric acid to yield the hydrochloridesalt. When this hydrochloride is catalytically hydrogenated, using theprocedure described above in Example 2B, there is obtained3-(isovaleryloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 77

Following a procedure similar to that described in Example 2A above,when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is interacted with 3,3-dimethylbutanecarbonylchloride there is obtained3-(3,3-dimethylbutanecarbonyloxy)-4-(p-toluyloxy)phenyltert-butylaminomethyl ketone which reacts with hydrochloric acid toyield the hydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 2B, thereis obtained3-(3,3-dimethylbutanecarbonyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 78

Following a procedure similar to that described in Example 2A above,when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with docosanoyl chloride there isobtained 3-(docosanoyloxy)-4-(p-tolulyloxy)phenyl tert-butylaminomethylketone which reacts with methanesulfonic acid to yield themethanesulfonate salt. When this methanesulfonate is catalyticallyhydrogenated, using the procedure described above in Example 2B, thereis obtained3-(docosanoyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate.

EXAMPLE 79

Following a procedure similar to that described in Example 30A above,when 3-hydroxy-4-(7,7-dimethyloctanoyloxy)phenyl tert-butylaminomethylketone is interacted with one equivalent of sodium methoxide and theresulting sodium phenolate salt is reacted with p-isopropoxyphenylacetylchloride there is obtained3-(p-isopropoxyphenylacetoxy)-4-(7,7-dimethyloctanoyloxy)phenyltert-butylaminomethyl ketone which reacts with methanesulfonic acid toyield the methanesulfonate salt. When this methanesulfonate iscatalytically hydrogenated, using the procedure described above inExample 30B, there is obtained3-(p-isopropoxyphenylacetoxy)-4-(7,7-dimethyloctanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate.

EXAMPLE 80

Following a procedure similar to that described above in Example 30A,when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone isinteracted with nicotinolyl chloride, there is obtained3-(nicotinoyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone;and by interaction of this base with hydrochloric acid there is obtainedthe hydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 30B, thereis obtained3-nicotinoyloxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 81

Following a procedure similar to that described in Example 2A above,when 3-hydroxy-4-(nicotinoyloxy)phenyl tert-butylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with 9-octadecenoyl chloride there isobtained 3-(9-octadecenoyloxy)-4-(nicotinoyloxy)phenyltert-butylaminomethyl ketone which reacts with methanesulfonic acid toyield the methanesulfonate salt. When this methanesulfonate is reducedwith sodium borohydride using the procedure described above in Example30C, there is obtained3-(9-octadecenoyloxy)-4-(nicotinoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate.

EXAMPLE 82

Following a procedure similar to that described in Example 13A above,when 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with 1,3-dimethylcyclobutanecarbonylchloride there is obtained3-(1,3-dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy)phenyltert-butylaminomethyl ketone which reacts with hydrochloric acid toyield the hydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 13B, thereis obtained3-(1,3-dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 83

A. Under an atmosphere of nitrogen, 8.4 g. of sodium methoxide is addedwith vigorous stirring to 16.8 g. of 3,4-dihydroxyphenylisopropylaminomethyl ketone hydrochloride suspended in 200 ml. ofN,N-dimethylformamide. About 20 ml. of solvent is distilled from thereaction mixture under reduced pressure to remove methyl alcohol. Then,under an atmosphere of nitrogen, 16 g. of 2,2-dimethylpentanoyl chlorideis dripped in slowly at 5° C. with vigorous stirring, and stirring iscontinued for one hour after all of the acid chloride has been added.The solvent is distilled off under reduced pressure and the resultingresidue is partitioned between water and diethyl ether. The ether layeris separated and washed with water, and the ether is distilled off toyield 3,4-bis(2,2-dimethylpentanoyloxy)phenyl isopropylaminomethylketone. This product is treated with hydrochloric acid in isopropylalcohol, and the solvent is evaporated to yield3,4-bis(2,2-dimethylpentanoyloxy)phenyl isopropylaminomethyl ketonehydrochloride.

B. A solution of 3,4-bis(2,2-dimethylpentanoyloxy)-phenylisopropylaminomethyl ketone hydrochloride in anhydrous ethyl alcohol ishydrogenated in the presence of 10 percent palladium-on-charcoalhydrogenation catalyst until one mole equivalent of hydrogen has beenabsorbed. The hydrogenation mixture is filtered to remove the catalyst,the solvent is evaporated from the filtrate, and isopropyl acetate isadded to the residue and then distilled off. The residue thus obtainedis dissolved in boiling isopropyl acetate and the solution thus obtainedis cooled. The precipitate which forms is collected on a filter, washedwith isopropyl acetate and with diethyl ether, and dried at 70° C. Thereis thus obtained3,4-bis(2,2-dimethylpentanoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride as a white crystalline powder.

EXAMPLE 84

When 7,7-dimethyloctanoyl chloride is substituted for the isobutyrylchloride in the procedure described in Example 2A above, the productobtained is 3,4-bis(7,7-dimethyloctanoyloxy)phenyl isopropylaminomethylketone; and by interaction of this base with methanesulfonic acid thereis obtained the methanesulfonate salt. When this methanesulfonate iscatalytically hydrogenated using the procedure described in Example 2Babove, there is obtained3,4-bis(7,7-dimethyloctanoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol methanesulfonate.

EXAMPLE 85

When hexadecanoyl chloride is substituted for the isobutyryl chloride inthe procedure described in Example 2A above, the product obtained is3,4-bis(hexadecanoyloxy)phenyl isopropylaminomethyl ketone; and byinteraction of this base with methanesulfonic acid there is obtained themethanesulfonate salt. When this methanesulfonate is catalyticallyhydrogenated using the procedure described in Example 2B above, there isobtained 3,4-bis(hexadecanoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol methanesulfonate.

EXAMPLE 86

When docosanoyl chloride is substituted for the isobutyryl chloride inthe procedure described in Example 2A above, the product obtained is3,4-bis(docosanoyloxy)phenyl isopropylaminomethyl ketone; and byinteraction with methanesulfonic acid there is obtained themethanesulfonate salt. When this methanesulfonate is catalyticallyhydrogenated using a procedure similar to that described in Example 2Babove, there is obtained3,4-bis-(docosanoyloxy)-alpha-(isopropylaminomethyl)benzyl alcoholmethanesulfonate.

EXAMPLE 87

Following the procedure described above in Example 2A but using4-methylcyclohexaneacetyl chloride instead of isobutyryl chloride thereis obtained 3,4-bis(4-methylcyclohexaneacetoxy)phenylisopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similarto that described above in Example 2B, there is obtained3,4-bis(4-methylcyclohexaneacetoxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 88

When cycloheptanecarbonyl chloride is substituted for the isobutyrylchloride in the procedure described in Example 2A above, the productobtained is 3,4-bis(cycloheptanecarbonyloxy)phenyl isopropylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated using a procedure similar to that describedin Example 2B above, there is obtained3,4-bis(cycloheptanecarbonyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 89

When p-toluyl chloride is substituted for the isobutyryl chloride in theprocedure described in Example 2A above, the acylation product obtainedis 3,4-bis-(p-toluyloxy)phenyl isopropylaminomethyl ketone, m.p. 82°-85°C. (uncorr.). This base was treated with trifluoroacetic acid to yieldthe trifluoroacetate salt as a white crystalline solid which melted at193°-195° C. (uncorr.) When 24 g. of this trifluoroacetate wascatalytically hydrogenated using a procedure similar to that describedin Example 2B above there was obtained 19.5 g. of3,4-bis(p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcoholtrifluoroacetate, m.p. 115°-117° C. (uncorr.). A 15 g. portion of thissalt was converted to the free base which was then treated withmethanesulfonic acid to yield 10.5 g. of the methanesulfonate salt as awhite crystalline solid which melted at 114°-116° C. (uncorr.).

EXAMPLE 90

When phenylacetyl chloride is substituted for the isobutyryl chloride inthe procedure described in Example 2A above, the product obtained is3,4-bis(phenylacetoxy)phenyl isopropylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is catalyticallyhydrogenated using a procedure similar to that described in Example 2Babove, there is obtained3,4-bis(phenylacetoxy)-alpha-(isopropylaminomethyl)benzyl alcoholhydrochloride.

EXAMPLE 91

Following the procedure described above in Example 2A but using3,7-dimethyl-3,6-octadienoyl chloride instead of isobutyryl chloridethere is obtained 3,4-bis(3,7-dimethyl-3,6-octadienoyloxy)phenylisopropylaminomethyl ketone; and by interaction of this base withmethanesulfonic acid there is obtained the methanesulfonate salt. Whenthis base is reduced with sodium borohydride, using a procedure similarto that described above in Example 30C, there is obtained3,4-bis(3,7-dimethyl-3,6-octadienoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol. By catalytically hydrogenating3,4-bis)3,7-dimethyl-3,6-octadienoyloxy)phenyl isopropylaminomethylketone methanesulfonate, using a procedure similar to that describedabove in Example 30B, there is obtained3,4-bis(3,7-dimethyloctadecanoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol methanesulfonate.

EXAMPLE 92

When isonicotinoyl chloride is substituted for the isobutyryl chloridein the procedure described in Example 2A above, the product obtained is3,4-bis(isonicotinoyloxy)phenyl isopropylaminomethyl ketone; and byinteraction of this base with methanesulfonic acid there is obtained themethanesulfonate salt. When this methanesulfonate is catalyticallyhydrogenated using a procedure similar to that described in Example 2Babove, there is obtained3,4-bis(isonicotinoyloxy)-alpha-(isopropylaminomethyl)benzyl alcoholmethanesulfonate.

EXAMPLE 93

Following the procedure described above in Example 58A but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert.-butylaminomethyl ketone hydrochloride andoctanoyl chloride instead of isovaleryl chloride, there is obtained3-hydroxy-4-(octanoyloxy)phenyl isopropylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using a procedure similar to that described above inExample 2b, there is obtained3-hydroxy-4-(octanoyloxy)-alpha-(isopropylaminomethyl)-benzyl alcoholhydrochloride.

EXAMPLE 94

Following the procedure described above in Example 58A but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and3,3-dimethylcyclobutanecarbonyl chloride instead of isovalery chloride,there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)phenylisopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similarto that described above in Example 2B, there is obtained3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 95

Following the procedure described above in Example 58A but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert.-butylaminomethyl ketone hydrochloride andphenoxyacetyl chloride instead of isovaleryl chloride, there is obtained3-hydroxy-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone; and byinteraction of this base with methanesulfonic acid there is obtained themethanesulfonate salt. When this methanesulfonate is catalyticallyhydrogenated, using a procedure similar to that described above inExample 2B, there is obtained3-hydroxy-4-(phenoxyacetoxy)-alpha-(isopropylaminomethyl)benzyl alcoholmethanesulfonate.

EXAMPLE 96

Following the procedure described above in Example 58A but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and1-naphthalenecarbonyl chloride instead of isovaleryl chloride, there isobtained 3-hydroxy-4-(1-naphthalenecarbonyloxy)phenylisopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similarto that described above in Example 2B, there is obtained3-hydroxy-4-(1-naphthalenecarbonyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 97

Following the procedure described above in Example 58A but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride andp-toluyl chloride instead of isovaleryl chloride, there is obtained3-hydroxy-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained thehydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using a procedure similar to that described above inExample 2B, there is obtained3-hydroxy-4-(p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcoholhydrochloride.

EXAMPLE 98

Following a procedure similar to that described above in Example 58A butusing 3,4-dihydroxyphenyl isopropylamino-methyl ketone hydrochlorideinstead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketonehydrochloride, and nicotinoyl chloride instead of isovaleryl chloride,there is obtained 3-hydroxy-4-(nicotinoyloxy)phenyl isopropylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using a procedure similar to that describedabove in Example 2B, there is obtained3-hydroxy-4-(nicotinoyloxy)-alpha-(isopropylaminomethyl)benzyl alcoholhydrochloride.

EXAMPLE 99

Following the procedure described above in Example 58A but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and2,3,4-trimethylbenzoyl chloride instead of isovaleryl chloride, there isobtained 3-hydroxy-4-(2,3,4-trimethylbenzoyloxy)phenylisopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similarto that described above in Example 2B, there is obtained3-hydroxy-4-(2,3,4-trimethylbenzoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 100

Following the procedure described above in Example 58A, but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride andm-dimethylaminobenzoyl chloride instead of isovaleryl chloride, there isobtained 3-hydroxy-4-(m-dimethylaminobenzoyloxy)phenylisopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similarto that described above in Example 2B, there is obtained3-hydroxy-4-(m-dimethylaminobenzoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 101

Following the procedure described above in Example 58A but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride ando-propionamidobenzoyl chloride instead of isovaleryl chloride, there isobtained 3-hydroxy-4-(o-propionamidobenzoyloxy)phenylisopropylaminomethyl ketone; and by interaction of this base withmethanesulfonic acid there is obtained the methanesulfonate salt. Whenthis methanesulfonate is catalytically hydrogenated, using a proceduresimilar to that described above in Example 2B, there is obtained3-hydroxy-4-(o-propionamidobenzoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol and methanesulfonate.

EXAMPLE 102

Following the procedure described above in Example 58A but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and2-chloro-3-methoxy-4-methylbenzoyl chloride instead of isovalerylchloride, there is obtained3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenylisopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similarto that described above in Example 2B, there is obtained3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 103

Following the procedure described above in Example 58A but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and10,13-octadecadienoyl chloride instead of isovaleryl chloride, there isobtained 3-hydroxy-4-(10,13-octadec a dienoyloxy) phenylisopropylaminomethyl ketone; and by interaction of this base withmethanesulfonic acid there is obtained the methanesulfonate salt. Whenthis methanesuflonate is reduced with sodium borohydride, using aprocedure similar to that described above in Example 30C, there isobtained3-hydroxy-4-(10,13-octadecadienoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol methanesulfonate. By catalytic hydrogenation of3-hydroxy-4-(10,13-octadienoyloxy)phenyl isopropylaminomethyl ketonemethanesulfonate, using a procedure similar to that described above inExample 30B, there is obtained3-hydroxy-4-(octadecanoyloxy)-alpha-(isopropylaminomethyl)benzylmethanesulfonate.

EXAMPLE 104

Following a procedure similar to that described above in Example 2A,when 3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with 3,3-dimethylpentanoyl chloridethere is obtained 3-(3,3-dimethylpentanoyloxy)-4-(isovaleryloxy)phenylisopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similarto that described above in Example 2B, there is obtained3-(3,3-dimethylpentanoyloxy)-4-(isovaleryloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 105

Following the procedure described above in Example 58A but using3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride there isobtained 3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone.

Following a procedure similar to that described above in Example 2A,when 3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with p-toluyl chloride there isobtained 3-(p-toluyloxy)-4-(isovaleryloxy)phenyl isopropylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenerated, using a procedure similar to thatdescribed above in Example 2B, there is produced3-(p-toluyloxy)-4-(isovaleryloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 106

Following a procedure similar to that described above in Example 2A,when 3-hydroxy-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with picolinoyl chloride, there isobtained 3-(picolinoyloxy)-4-(p-toluyloxy)phenyl isopropylaminomethylketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, usign a procedure similar to that describedabove in Example 2B, there is obtained3-(picolinoyloxy)-4-(p-toluyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 107

Following a procedure similar to that described in Example 2A above,when 3-hydroxy- 4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenylisopropylaminomethyl ketone is interacted with one equivalent of sodiummethoxide and the resulting sodium phenolate salt is reacted withisovaleryl chloride there is obtained3-(isovaleryloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenylisopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similarto that described above in Example 2B, there is obtained3-(isovaleryloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 108

Following a procedure similar to that described above in Example 2A,when 3-hydroxy-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone isinteracted with one equivalent of sodium methoxide and the resultingsodium phenolate salt is reacted with cyclohexanecarbonyl chloride thereis obtained 3-(cyclohexanecarbonyloxy)-4-(phenoxyacetoxy)phenylisopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similarto that described above in Example 2B, there is obtained3-(cyclohexanecarbonyloxy)-4-(phenoxyacetoxy)-alpha-(isopropylaminomethyl)-benzylalcohol hydrochloride.

EXAMPLE 109

Following a procedure similar to that described above in Example 2A,when 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenylisopropylaminomethyl ketone is interacted with one equivalent of sodiummethoxide and the resulting sodium phenolate is reacted with3,3-dimethylheptadecanoyl chloride there is obtained3-(3,3-dimethylheptadecanoyloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenylisopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similarto that described above in Example 2B, there is obtained3-(3,3-dimethylheptadecanoyloxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 110

Following a procedure similar to that described in Example 2A above when3-hydroxy- 4-(3,3-dimethylcyclobutanecarbonyloxy)phenylisopropylaminomethyl ketone is interacted with one equivalent of sodiummethoxide and the resulting sodium phenolate salt is reacted with2,5-hexadienoyl chloride there is obtained3-(2,5-hexadienoyloxy)-4-(3,3-dimethylcyclobutanecarbonyloxy)phenylisopropylaminomethyl ketone which reacts with hydrochloric acid to yieldthe hydrochloride salt. When this hydrochloride is reduced with sodiumborohydride, using a procedure similar to that described above inExample 30C, there is obtained3-(2,5-hexadienoyloxy)-4-(3,3-dimethylcyclobutanecarbonyloxy)-alpha-(isopropylaminomethyl)benzylalcohol hydrochloride.

EXAMPLE 111

A mixture of 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketonehydrochloride, 25 m. of o-toluyl chloride, and 35 ml. of trifluoroaceticacid was heated for 30 minutes on a steam bath. The reaction mixture wasconcentrated under reduced pressure, and the resulting residuecrystallized. This solid, which was crude 3,4-bis(o-toluyloxy)phenyltert-butylaminomethyl ketone trifluoroacetate, was slurried in anhydrousethyl ether and the slurry was made basic by treatment with ammoniumhydroxide. The ether layer was separated and washed first with diluteaqueous sodium hydroxide solution and then with water. The ethersolution was filtered and the filtrate was slurried with 4.5 g. ofmethanesulfonic acid in 50 ml. of isopropyl alcohol. The crystallinesolid which precipitated was collected on a filter and recrystallizedfrom 100 ml. of isopropyl alcohol and dried at 70° C. There was thusobtained 15.8 g. of 3,4-bis(o-toluyloxy)phenyl tert-butylaminomethylketone methanesulfonate as a white crystalline solid which melted at134°-137° C. (dec.)(uncorr.). When this methanesulfonate (15.5 g.) wascatalytically hydrogenated, using a procedure similar to that describedabove in Example 30B, there was obtained 12.8 g. of3,4-bis(o-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 151°-153°C. (uncorr.).

EXAMPLE 112

Following a procedure similar to that described above in Example 111 butusing m-toluyl chloride instead of o-toluyl chloride, there was obtained14 g. of 3,4-bis(m-toluyloxy)phenyl tert-butylaminomethyl ketonehydrochloride as a white crystalline solid which melted at 215°-218° C.When 19 g. of this hydrochloride (5 g. of which was obtained from asecond run) was catalytically hydrogenated, using a procedure similar tothat described above in Example 30B, there was obtained3,4-bis(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride which was converted to the free base and then to themethanesulfonate, a white crystalline solid which weighed 12.0 g. andmelted at 135° C. (uncorr.).

EXAMPLE 113

Following a procedure similar to that described above in Example 111, 14g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride wasreacted with 27 g. of 2,3-dimethylbenzoyl chloride in 50 ml. oftrifluoroacetic acid to yield 3,4-bis(2,4-dimethylbenzoyloxy)phenyltert-butylaminomethyl ketone trifluoroacetate. This salt was convertedto the free base by treatment with sodium hydroxide solution and thefree base was interacted with methanesulfonic acid to yield 22 g. of3,4-bis(2,4-dimethylbenzoyloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate as a white crystalline solid which melted at 120°-123°C. (dec.)(uncorr.). This salt (20 g.) was catalytically hydrogenated inN,N-dimethylformamide using a procedure similar to that described abovein Example 30B, to yield 18 g. of3,4-bis(2,4-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at170°-172° C. (uncorr.).

EXAMPLE 114

Following a procedure similar to that described above in Example 111, 20g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride wasreacted with 37 g. of 2,5-dimethylbenzoyl chloride in 50 ml. oftrifluoroacetic acid to yield 3,4-bis(2,5-dimethylbenzoyloxy)phenyltert-butylaminomethyl ketone trifluoroacetate. This salt was convertedto the free base by treatment with ammonium hydroxide and the free basewas interacted with methanesulfonic acid to yield 38 g. of3,4-bis(2,5-dimethylbenzoyloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate as a white crystalline solid which melted at 134°-137°C. (dec.)(uncorr.). This salt (37 g.) was catalytically hydrogenated inN,N-dimethylformamide, using a procedure similar to that described abovein Example 30B, to yield 30 g. of3,4-bis(2,5-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at156°-158° C. (uncorr.).

EXAMPLE 115

Following a procedure similar to that described above in Example 111, 20g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride wasreacted with 37 g. of 3,4-dimethylbenzoyl chloride in 50 ml. oftrifluoroacetic acid to yield 3,4-bis(3,4-dimethylbenzoyloxy)phenyltert-butylaminomethyl ketone trifluoroacetate. This salt was convertedto the free base by treatment with ammonium hydroxide and the free basewas interacted with methanesulfonic acid to yield 33 g. of3,4-bis-(3,4-dimethylbenzoyloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate as a white crystalline solid which melted at 119°-122°C. (uncorr.). This salt (32 g.) was catalytically hydrogenated, using aprocedure similar to that described above in Example 30B, to yield 28.0g. of3,4-bis(3,4-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at212° C.

EXAMPLE 116

Following a procedure similar to that described above in Example 111, 20g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride wasreacted with 37 g. of 3,5-dimethylbenzoyl chloride in 50 ml. oftrifluoroacetic acid to yield 3,4-bis(3,5-dimethylbenzoyloxy)phenyltert-butylaminomethyl ketone trifluoroacetate. This salt was convertedto the free base by treatment with ammonium hydroxide and the free basewas interacted with methanesulfonic acid to yield 29 g. of3,4-bis(3,5-dimethylbenzoyloxy)phenyl tert-butylaminomethyl ketonemethane sulfonate as a white crystalline solid which melted at 123°-128°C. This salt (28 g.) was catalytically hydrogenated inN,N-dimethylformamide, using a procedure similar to that described abovein Example 30B, to yield 25 g. of3,4-bis(3,5-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at190°-193° C. (uncorr.).

EXAMPLE 117

A mixture of 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketonehydrochloride, 26 g. of p-tolylacetyl chloride and 40 g. oftrifluoroacetic acid was refluxed for 1 hour and then the volatilematerial was removed from the reaction mixture by heating under reducedpressure. The resulting residue, which was crude3,4-bis(p-tolylacetoxy)phenyl tert-butylaminomethyl ketonetrifluoroacetate, was slurried in diethyl ethyl-dilute ammoniumhydroxide, after which the ether layer was separated, washed first withdilute sodium hydroxide solution and then with water, and shaken with aslight excess of dilute hydrochloric acid. The crystalline precipitatewhich formed was collected on a filter, washed with diethyl ether, anddried at 60° C. There was thus obtained 21 g. of3,4-bis(p-tolylacetoxy)phenyl tert-butylaminomethyl ketone hydrochlorideas a white crystalline solid which melted at 205°-208° C.(dec.)(uncorr.). This salt was catalytically hydrogenated, using aprocedure similar to that described above in Example 30B, to yield 16 g.of 3,4-bis-(p-tolylacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride as a white crystalline solid which melted at 115°-117° C.(uncorr.).

EXAMPLE 118

Following a procedure similar to that described above in Example 117, 13g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride wasreacted with 20 g. of p-methoxyphenylacetyl chloride in 50 ml. oftrifluoroacetic acid and the resulting product was worked up to yield 14g. of 3,4-bis(p-methoxyphenylacetoxy)phenyl tert-butylaminomethyl ketonehydrochloride as a white crystalline solid which melted at 204°-207° C.(dec.)(uncorr.). This salt (13.5 g.) was catalytically hydrogenated,using a procedure similar to that described above in Example 30B. toyield 8.8 g. of3,4-bis(p-methoxyphenylacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride as a white crystalline solid which melted at124°-127° C. (uncorr.).

EXAMPLE 119

Using a procedure similar to that described above in Example 58A, 26 g.of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 300ml. of N,N-dimethylformamide under an atmosphere of nitrogen was reactedwith 16 g. of sodium methoxide and then with 14 g. of benzoyl chloride.The product was isolated as the free base,3-hydroxy-4-(benzoyloxy)phenyl tert-butylaminomethyl ketone [20 g; m.p.150°-165° C. (dec.)(uncorr.)], which was converted to 13 g. of itsmethanesulfonate, m.p. 245° C. (dec.)(uncorr.). By catalyticallyhydrogenating this salt, using a procedure similar to that describedabove in Example 30B, there is obtained3-hydroxy-4-(benzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate.

EXAMPLE 120

Using a procedure similar to that described above in Example 58A, 26 g.of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride wasreacted with 16 g. of sodium methoxide in N,N-dimethylformamide under anatmosphere of nitrogen and then 17 g. of p-anisoyl chloride was added toproduce 35 g. of 3-hydroxy-4-(p-anisoyloxy)phenyl tert-butylaminomethylketone, m.p. 170°-175° C. (dec.)(uncorr.), which was converted to 28 g.of the hydrochloride, m.p. 235° C. (dec.)(uncorr.). This hydrochloride(26 g.) was catalytically hydrogeated, using a procedure similar to thatdescribed above in Example 30B, to yield 19 g. of3-hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride as a white crystalline solid which melted at 211°-213° C.(dec.)(uncorr.). By interacting this hydrochloride with p-anisoylchloride and with acetyl chloride, there are obtained3-hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl p-anisatehydrochloride and3-hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl acetatehydrochloride, respectively.

EXAMPLE 121

A mixture of 20 g. of 3-hydroxy-4-(p-toluyloxy)phenyltert-butylaminomethyl ketone methanesulfonate, 100 ml. of acetylchloride, and 200 ml. of acetic acid was refluxed and stirred for twohours and then the volatile material was removed from the reactionmixture by heating under reduced pressure. The resulting residue wascrystallized from isopropyl acetate to yield 20 g. of3-acetoxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate as a white crystalline solid which melted at 204°-207°C. (uncorr.). This salt was catalytically hydrogenated inN,N-dimethylformamide, using a procedure similar to that described abovein Example 30B, to yield 14.0 g. of3-acetoxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 171°-173°C. (uncorr.).

EXAMPLE 122

A mixture of 12.5 g. of 3-hydroxy-4-(benzoyloxy)phenyltert-butylaminomethyl ketone methanesulfonate, 13 g. of p-toluylchloride, and 35 ml. of trifluoroacetic acid was refluxed for one hourand then the volatile material was removed from the reaction mixtureunder reduced pressure. The resulting solid residue was slurried indiethyl ether-Water and the slurry was filtered to collect 17.1 g. of3-(p-toluyloxy)-4-(benzoyloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate as a white crystalline solid which melted at 205°-210°C. (dec.)(uncorr.). This salt (17 g.) was catalytically hydrogenated inN,N-dimethylformamide, using a procedure similar to that described abovein Example 30B, to yield 9.3 g. of3-(p-toluyloxy)-4-benzoyloxyalpha-(tert-butylaminomethyl)benzyl alcoholtrifluoroacetate, m.p. 162°-166° C. which was converted via the freebase, to 7.1 g. of the methanesulfonate, a white crystalline solid whichmelted at 154°-156° C. (uncorr.).

EXAMPLE 123

A mixture of 18.5 g. of 3-hydroxy-4-(p-toluyloxy)phenyltert-butylaminomethyl ketone methanesulfonate, 12 ml. of benzoylchloride, and 35 ml. of trifluoroacetic acid was refluxed for one hourand then the volatile material was removed from the reaction mixture byheating under reduced pressure. The residual gum, which was crude3-benzoyloxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketonemethansulfonate, was slurried with diethyl ether, the ether was removedby decantation, and the gum was dissolved by stirring it with diethylether-dilute ammonium hydroxide. The ether layer was separated, washedwith dilute sodium hydroxide solution, and dried with ground cellulosefiber. The ether solution was mixed with a solution of 5 g. ofmethanesulfonic acid in 25 ml. of isopropyl alcohol, thereby causingprecipitation of a syrup which rapidly solidified. This solid wascollected and dissolved in 50 ml. of isopropyl alcohol, and the solutionwas diluted with diethyl ether and stirred. The crystalline solid whichformed was collected on a filter, washed with a small amount ofisopropyl alcohol-diethyl ether mixture, and dried. There was thusobtained 13 g. of 3-benzoyloxy-4 -(p-toluyloxy)phenyltert-butylaminomethyl ketone methanesulfonate hydrate as a whitecrystalline solid which softened at 115° C. (uncorr.). This salt wascatalytically hydrogenated, using the procedure described above inExample 30B, to yield 8.5 g. of3-benzoyloxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 183°-185°C. (uncorr.).

EXAMPLE 124

To 50 g. of N-benzyl-N-methylamine in 200 ml. of N,N-dimethylformamidethere was added portionwise 37.2 g. of3,4-dihydroxy-alpha-chloroacetophenone with occasional swirling of themixture. The mixture was allowed to stand for thirty minutes and thenwas warmed to 70° C. and the N,N-dimethylformamide was distilled off.The resulting residue was slurried in 400 ml. of water and the solidproduct was collected on a filter and washed with water and diethylether. By treating the 3,4-dihydroxyphenyl N-benzyl-N-methylaminomethylketone thus obtained with methanesulfonic acid there was obtained 54.5g. of the methanesulfonate salt, m.p. 154°-155° C. (uncorr.). Using aprocedure similar to that described above in Example 58A, 36.8 g. ofthis salt was reacted with 16.2 g. of sodium methoxide inN,N-dimethylformamide under an atmosphere of nitrogen and the 16 g. ofp-toluyl chloride was added to produce 3-hydroxy-4-(p-toluyloxy)phenylN-benzyl-N-methylaminomethyl ketone, which by treatment withmethanesulfonic acid was converted to 32 g. of the methanesulfonate,m.p. 214°-216° C. (uncorr.). The N-benzyl group was removed from thisproduct by catalytic hydrogenation in the presence of 2 g. of 10 percentpalladium-on-charcoal catalyst until the calculated one mole equivalentof hydrogen was absorbed. There was thus obtained 20 g. of3-hydroxy-4-(p-toluyloxy)phenyl methylaminomethyl ketonemethanesulfonate, m.p. 188°-189° C. (uncorr.). This salt wascatalytically hydrogenated in 200 ml. of 95 percent ethyl alcohol at 25°C. in the presence of 2 g. of 10 percent palladium-on-charcoalhydrogenation catalyst until 1 mole equivalent of hydrogen was absorbed.This required eight hours, during the last 3 hours of which period thereaction mixture was heated at 50° C. There was thus obtained 12.3 g. of3-hydroxy-3-(p-toluyloxy)alpha-(methylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 185° C.(uncorr.).

EXAMPLE 125

Using a procedure similar to that described above in Example 3A,3,4-dihydroxyphenyl N-benzyl-N-methylaminomethyl ketone methanesulfonateis reacted with two mole equivalents of 2,2-dimethylpentanoyl chloridein 2,2-dimethylpentanoic acid to yield3,4-bis(2,2-dimethylpentanoyloxy)phenyl N-benzyl-N-methylaminomethylketone methanesulfonate as a white crystalline solid. This salt isdebenzylated by catalytic hydrogenation in the presence ofpalladium-on-charcoal hydrogenation catalyst, in the same manner as thedebenzylation procedure described above in Example 124, to yield3,4-bis(2,2-dimethylpentanoyloxy)phenyl methylaminomethyl ketonemethanesulfonate as a white crystalline solid. This salt iscatalytically hydrogenated in anhydrous ethyl alcohol in the presence of10 percent palladium-on-charcoal hydrogenation catalyst until one moleequivalent of hydrogen is absorbed. There is thus obtained3,4-bis(2,2-dimethylpentanolyoxy)-alpha-(methylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid.

EXAMPLE 126

Following a procedure similar to that described above in Example 111,18.5 g. of 3,4-dihydroxyphenyl N-benzyl-N-methylaminomethyl ketonemethanesulfonate was reacted with 16 g. of p-toluyl chloride in 35 ml.of trifluoroacetic acid to yield 33 g. of 3,4-bis(p-toluyloxy)phenylN-benzyl-N-methylaminomethyl ketone methanesulfonate. This salt wasdebenzylated by catalytic hydrogenation in the presence ofpalladium-on-charcoal hydrogenation catalyst, in the same manner as thedebenzylation procedure described above in Example 124, to yield 21.6 g.of 3,4-bis-p-toluyloxy)phenyl methylaminomethyl ketone methanesulfonate,m.p. 195°-197° C. (uncorr.). This salt was catalytically hydrogenated,using the procedure described above in Example 30B, to yield 13.8 g. of3,4-bis(p-toluyloxy)-alpha-(methylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which is melted at110°-112° C. (uncorr.).

EXAMPLE 127

A. A mixture of 40 g. of 3,4-dihydroxy-alpha-chloroacetophenone, 86 g.of dibenzylamine, and 300 ml. of anhydrous isopropyl alcohol wasrefluxed for four hours. After adding 300 ml. of anhydrous diethylether, the reaction mixture was cooled, the solid (dibenzylaminehydrochloride) which precipitated was removed by filtration, and thefiltrate was evaporated to dryness. The resulting residue was dissolvedin 800 ml. of isopropyl acetate and this solution was washed with three250 ml. portions of water and then dried over sodium sulfate. To the drysolution there was added 500 ml. of isopropyl alcohol and the mixturewas acidified by addition of an isopropyl alcohol solution of hydrogenchloride and cooled. The solid (another portion of dibenzylaminehydrochloride) which separated was removed by filtration and thefiltrate was concentrated under reduced pressure and acetone was addedto the residue, which solidified. This solid was collected on a filter.There was thus obtained 54 g. of 3,4-dihydroxyphenylN,N-dibenzylaminomethyl ketone hydrochloride which melted at 196°-198°C. (uncorr.). Using a procedure similar to that described above inExample 111 this product (35 g.) was reacted with 40 g. of p-toluylchloride in 50 ml. of trifluoroacetic acid, and the resultingester-amine salt was converted to the free ester-amine by treatment withammonium hydroxide, and the free ester-amine was treated with anisopropyl alcohol solution of hydrogen chloride to yield 38 g. of3,4-bis(p-toluyloxy)phenyl N,N-dibenzylaminomethyl ketone hydrochloridewhich melted at 165°-172° C. (dec.)(uncorr.).

B. To 40 g. of 3,4-bis(p-toluyloxy)phenyl N,N-dibenzylaminomethyl ketonehydrochloride in 750 ml. of anhydrous methyl alcohol stirred at 0°-3° C.in an ice-bath there was gradually added, over a period of 20 minutes,10 g. of sodium borohydride. The reaction mixture was stirred in anice-bath for one hour, then was acidified by addition of 13 ml. ofglacial acetic acid, and the solvent was removed by evaporation underreduced pressure. The solid residue thus obtained was taken up in amixture of 250 ml. of water, 25 ml. of concentrated ammonium hydroxide,and 400 ml. of diethyl ether. The ether layer was separated, washed withtwo 60 ml. portions of water, dried over sodium sulfate, andconcentrated by evaporation under reduced pressure. The oily residuethus obtained, which was crude3,4-bis(p-toluyloxy)-alpha-(N,N-dibezylaminomethyl)benzyl alcohol, wasdissolved in 150 ml. of isopropyl alcohol and 25 ml of an ethyl alcoholsolution of hydrogen chloride. The solvent was removed by evaporationunder reduced pressure and the resulting residue was stirred in 170 ml.of anhydrous isopropyl alcohol while heating on a steam bath. Thecrystalline solid which precipitated was collected on a filter. Thisproduct, which weighed 35 g., was dissolved in 850 ml. of boiling methylalcohol and the solution was concentrated by evaporation under reducedpressure until the solution became cloudy (volume reduced about 200 ml.)and cooled in an ice-bath. The solid which crystallized out wascollected on a filter. There was thus obtained 25 g. of3,4-bis(p-toluyloxy)-alpha-(N,N-dibenzylaminomethyl)benzyl alcoholhydrochloride as a white crystalline solid which melted at 221°-223° C.(uncorr.). This salt (24 g.) was converted to the free base by treatmentwith ammonium hydroxide and the free base was dissolved in 100 ml. ofisopropyl alcohol and treated with 3.67 g. of methanesulfonic acid in 25ml. of anhydrous isopropyl alcohol. The solvent was removed byevaporation under reduced pressure and the methanesulfonate thusobtained was debenzylated by catalytic hydrogenation in anhydrous ethylalcohol in the presence of 10 percent palladium-on-charcoalhydrogenation catalyst, in the earlier stages at room temperature andthen later at 50° C. After removal of the catalyst, the hydrogenationmixture was concentrated under reduced pressure to a volume ofapproximately 75 ml. The crystalline precipitate which formed was mixedwith 100 ml. of acetone and the mixture was filtered. The solid thuscollected, which weighed 18 g. and melted at 176°-180° C. (uncorr.), wasrecrystallized from a mixture of equal parts of acetone and anhydrousethyl alcohol to yield 16 g. of3,4-bis(p-toluyloxy)-alpha-(aminomethyl)benzyl alcohol methanesulfonateas a white crystalline solid which melted at 178°-181° C. (uncorr.).

EXAMPLE 128

A. Using a procedure similar to that described above in Example 2A,3,4-dihydroxyphenyl N,N-dibenzylaminomethyl ketone hydrochloride isreacted with two mole equivalents of sodium methoxide and the resultingsodium phenolate product is reacted with two equivalents of2,2-dimethylpentanoyl chloride to yield3,4-bis(2,2-dimethylpentanoyloxy)phenyl N,N-dibenzylaminomethyl ketonehydrochloride.

B. To 3,4-bis(2,2-dimethylpentanoyloxy)phenyl N,N-dibenzylaminomethylketone hydrochloride in anhydrous methyl alcohol stirred at 3°-7° C.there is added portionwise, over a period of 30 minutes, sodiumborohydride. Stirring for a further period of 1 hour is continued at3°-7° C. The reaction mixture is neutralized by addition of glacialacetic acid. The mixture is the concentrated under reduced pressure toyield a solid residue which is taken up in a mixture of water, diethylether, and ammonium hydroxide and filtered. The ether layer in thefiltrate is separated, washed with water, dried over sodium sulfate, andevaporated under reduced pressure. The residue thus obtained isdissolved in isopropyl alcohol, an isopropyl alcohol solution ofhydrogen chloride is added, and the solution is cooled. The solid whichseparates the solution is collected on a filter, washed with acetone andwith diethyl ether, and dried at 60° C. There is thus obtained3,4-bis(2,2-dimethylpentanoyloxy)-alpha-(N,N-dibenzylaminomethyl)benzylalcohol hydrochloride as a white crystalline solid. This hydrochlorideis converted to the free base by treatment with ammonium hydroxide, andthe free base is treated with methanesulfonic acid to produce themethanesulfonate. This salt is debenzylated by catalytic hydrogenationin anhydrous ethyl alcohol in the presence of 10 percentpalladium-on-charcoal hydrogenation catalyst to yield3,4-bis(2,2-dimethylpentanoyloxy)-alpha-(aminomethyl)benzyl alcoholmethanesulfonate.

EXAMPLE 129

Using a procedure similar to that described above in Example 111, 9 g.of 3,4-dihydroxyphenyl 1-(tert-butylamino)ethyl ketone hydrochloride wasreacted with 16 ml. of p-toluyl chloride in 25 ml. of trifluoroaceticacid and the resulting product was worked up to yield 11 g. of3,4-bis(p-toluyloxy)phenyl 1-(tert-butylamino)ethyl ketone hydrochlorideas a white crystalline solid which melted at 225°-228° C.(dec.)(uncorr.). This salt was catalytically hydrogenated, using aprocedure similar to that described above in Example 30B, to yield 6.1g. of 3,4-bis-(p-toluyloxy)-alpha-[1-(tert-butylamino)ethyl]benzylalcohol hydrochloride as a white crystalline solid which melted at 228°C. (uncorr.).

EXAMPLE 130

A. A mixture of 50 g. of 3,4-bis(benzyloxy)-alpha-bromopropiophenone[m.p. 92°-93.5° C. (uncorr.); obtained by brominating3,4-bis(benzyloxy)propiophenone with bromine in methylene chloride], 50ml. of tert-butylamine, 250 ml. of N,N-dimethylformamide was allowed tostand at room temperature for twenty-four hours. The mixture was thenpoured into 1500 ml. of water. The solid which precipitated, which was3,4-bis(benzyloxy)phenyl 1-(tert-butylamino)ethyl ketone, was convertedto 50 g. of the hydrochloride, m.p. 157°-159° C. (uncorr.). This saltwas catalytically hydrogenated in 250 ml. of 95 percent ethyl alcohol inthe presence of 2 g. of 10 percent palladium-on-charcoal hydrogenationcatalyst until the theoretical quantity of hydrogen required for removalof the two benzyl groups was absorbed. This reduction requiredapproximately one-half hour. The resulting product, which was3,4-dihydroxyphenyl 1-(tert-butylamino)ethyl ketone hydrochloride, afterslurrying in isopropyl acetate, was a white crystalline solid whichweighed 28 g. and melted at 237°-239° C. (dec.)(uncorr.).

B. A 10 g. portion of 3,4-dihydroxyphenyl 1-(tert-butylamino)ethylketone hydrochloride was catalytically hydrogenated in 200 ml. of 95percent ethyl alcohol in the presence of 10 percentpalladium-on-charcoal hydrogenation catalyst until one mole equivalentof hydrogen was absorbed. This required 8 hours, with heating during thelast three hours. By removal of the catalyst and isolation of thereduction product there was obtained 6 g. of3,4-dihydroxy-alpha-[1-(tert-butylamino)ethyl]benzyl alcoholhydrochloride as a white crystalline solid which melted at 216° C.(uncorr.).

C. A mixture of 13.5 g. of 3,4-dihydroxyphenyl 1-(tert-butylamino)ethylketone hydrochloride, 18 g. of isovaleryl chloride, and 50 ml. oftrifluoroacetic acid was refluxed for one hour and then the volatilematerial was evaporated from the reaction mixture under reducedpressure. The resulting residue was slurried in diethyl ether-diluteammonium hydroxide. The ether layer was separated, washed first withdilute sodium hydroxide solution and then with water, and evaporated toyield a residue which was taken up in 50 ml. of isopropyl alcohol and 4ml. of concentrated hydrochloric acid. The resulting solution wasevaporated under reduced pressure and the residue thus obtained wascrystallized from isopropyl acetate to yield 13 g. of3,4-bis-(isovaleryloxy)phenyl 1-(tert-butylamino)ethyl ketonehydrochloride as a white crystalline solid which melted at 181°-183° C.(uncorr.). This salt was catalytically hydrogenated, using a proceduresimilar to that described above in Example 30B, to yield 10 g. of3,4-bis(isovaleryloxy)-alpha-[1-(tert-butylamino)ethyl]benzyl alcoholhydrochloride as a white crystalline solid which melted at 152° C.(uncorr.).

EXAMPLE 131

Using a procedure similar to that described above in Example 111, 13 g.of 3,4-dihydroxyphenyl 1-(isopropylamino)ethyl ketone hydrochloride[m.p. 141°-143° C. (uncorr.); obtained by interacting3,4-dibenzyloxy-alpha-bromopropriophenone with isopropylamine anddebenzylating the resulting 3,4-bis(benzyloxy)phenyl1-(isopropylamino)ethyl ketone hydrochloride, m.p. 215°-218° C.(uncorr.), by catalytic hydrogenation in the presence ofpalladium-on-charcoal] was interacted with 17 g. of p-toluyl chloride in40 ml. of trifluoroacetic acid, and the resulting ester-amine salt wasconverted to the free ester-amine by treatment with ammonium hydroxideand the free ester-amine was then treated with hydrochloric acid toyield 14 g. of 3,4-bis(p-toluyloxy)phenyl 1-(isopropylamino)ethyl ketonehydrochloride as a white crystalline solid which melted at 233°-235° C.(dec.) (uncorr.). This salt was catalytically hydrogenated, using aprocedure similar to that described above in Example 30B, to yield 12.5g. of 3,4-bis(p-toluyloxy)-alpha-[1-(isopropylamino)ethyl]benzyl alcoholhydrochloride as a white crystalline solid which melted at 228°-230° C.(dec.)(uncorr.).

EXAMPLE 132

Using a procedure similar to that described above in Example 111, 15 g.of 3,4-dihydroxyphenyl 1-(isopropylamino)propyl ketone hydrochloride wasreacted with 25 ml. of p-toluyl chloride in 40 ml. of trifluoroaceticacid, and the resulting ester-amine salt was converted to the freeester-amine by treatment with ammonium hydroxide and the freeester-amine was then treated with hydrochloric acid to yield 19.5 g. of3,4-bis(p-toluyloxy)phenyl 1-(isopropylamino) propyl ketonehydrochloride as a white crystalline solid which melted at 204°-207° C.(dec.) (uncorr.). This salt was catalytically hydrogenated, using theprocedure described above in Example 30B, to yield 14 g. of3,4-bis(p-toluyloxy)-alpha-[1-(isopropylamino)propyl]benzyl alcoholhydrochloride as a white crystalline solid which melted at 203°-205° C.(uncorr.).

EXAMPLE 133

Using a procedure similar to that described above in Example 111, 15 g.of 3,4-dihydroxyphenyl 1-(cyclopentylamino)propyl ketone hydrochloride[m.p. 108°-112° C. (uncorr.); obtained by interacting3,4-bis(benzyloxy)phenyl-alpha-bromobutyrophenone with cyclopentylamineand debenzylating the resulting 3,4-bis-(benzyloxy)phenyl1-(cyclopentylamino)propyl ketone, m.p. 150° C. (uncorr.), by catalytichydrogenation in the presence of palladium-on-charcoal] was reacted with25 ml. of p-toluyl chloride in 35 ml. of trifluoroacetic acid, and theresulting ester-amine salt was converted to the free ester-amine bytreatment with ammonium hydroxide and the free ester-amine was thentreated with hydrochloric acid to yield 18.9 g. of3,4-bis(p-toluyloxy)phenyl 1-(cyclopentylamino)-propyl ketonehydrochloride as a white crystalline solid which melted at 198°-201° C.(uncorr.). This salt (18.5 g.) was catalytically hydrogenated, using theprocedure described above in Example 30B, to yield 14.4 g. of3,4-bis(p-toluyloxy)-alpha-[1-(cyclopentylamino)-propyl]benzyl alcoholhydrochloride as a white crystalline solid which melted at 180° C.(uncorr.).

EXAMPLE 134

To 5.3 g. of 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate in 25 ml. of glacial acetic acid there wasadded 2.1 ml. of acetyl chloride, and the resulting mixture was shakenuntil complete solution was obtained. This solution was concentrated toyield a solid which was recrystallized from isopropyl acetate. There wasthus obtained the methanesulfonate of3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl acetate as awhite crystalline solid which weighed 1.2 g. and melted at 153°-155° C.(uncorr.).

EXAMPLE 135

A. A mixture of 130 g. of 3-chloromethyl-4-hydroxyacetophenone, 650 ml.of acetic anhydride, and 130 ml. of acetyl chloride was refluxed for 3hours and then the reaction mixture was concentrated and fractionallydistilled under reduced pressure. The fraction distilling at 135°-148°C. at 0.6 mm. Hg. pressure solidified. This product, which weighed 94.9g., was 3-chloromethyl-4-acetoxyacetophenone.

B. To 200 g. of pivalic acid there was added 17.1 g. of sodium methoxidein methyl alcohol and resulting reaction mixture was stripped of methylalcohol under reduced pressure. To the solid residue thus obtained therewas added 71.4 g. of 3-chloromethyl-4-acetoxyacetophenone and themixture was heated with stirring while allowing 110 ml. of material todistill off. The reaction mixture was concentrated under reducedpressure and cooled, and a mixture of water and diethyl ether was added.All except about 10 g. of gummy material dissolved. The ether layer wasseparated and washed three times with cold aqueous sodium bicarbonatesodium and once with water. The ether solution was then dried overanhydrous magnesium sulfate, concentrated, and distilled under reducedpressure. After a 4.1 g. forerun which was discarded, there was obtained44.9 g. of a fraction which distilled at 158°-168° C. at 0.1 mm. Hg.pressure. This product was slightly impure3-(pivalyloxymethyl)-4-(pivalyloxy)acetophenone.

C. To 43 g. of 3-(pivalyloxymethyl)-4-(pivalyloxy)acetophenone in 225ml. of chloroform there was gradually added, over a period of 30minutes, a solution of bromine in 40 ml. of chloroform. During thisaddition the temperature of the reaction mixture was maintained at 10°C. by the addition thereto of solid carbon dioxide. The chloroformsolution of the reaction mixture was washed twice with water, twice withdilute aqueous sodium bicarbonate solution, and finally once with water,dried over magnesium sulfate, and concentrated under reduced pressure.The resulting residue, which was 21.5 g. of crude3-(pivalyloxymethyl)-4-(pivalyloxy)-alpha-bromoacetophenone, was addedwith stirring to a solution of 9.45 ml. of tert-butylamine and 13.1 g oftriethylamine in 225 ml. of dimethyl sulfoxide. During this addition,the reaction mixture was stirred at 10°-15° C. and thereafter wasstirred at 20° C. for one-half hour. The mixture was poured into waterand extracted several times with diethyl ether. The ether extracts werecombined, dried, and concentrated. The gummy residue thus obtained,which was crude 3-(pivalyloxymethyl)-4-(pivalyloxy)phenyltert-butylaminomethyl ketone, was treated with 8.5 g. of methanesulfonicacid to yield 19.5 g. of 3-pivalyloxymethyl)-4-(pivalyloxy)phenyltert-butylaminomethyl ketone methanesulfonate as a white crystallinesolid which melted at 164°-173° C. (uncorr.).

D. To a solution of 2.5 g. of 3-(pivalyloxymethyl)-4-(pivalyloxy)phenyltert-butylaminomethyl ketone methanesulfonate in 30 ml of methyl alcoholat -10° C. there was added portionwise 0.3 g. of sodium borohydride. Thereaction mixture was then stirred for 10 minutes at -10° C. and glacialacetic acid was gradually added until the mixture was neutral. Themixture was then concentrated on a rotary evaporator and the resultingresidue was dissolved in 25 ml. of cold water. This solution was madeslightly basic by addition of ammonium hydroxide and extracted threetimes with diethyl ether. The ether extracts were combined, dried overanhydrous calcium sulfate, and concentrated under reduced pressure. Theresulting gummy residue was dissolved in 20 ml. of isopropyl acetate andto this solution were added 0.35 ml. of methanesulfonic acid and 1volume of diethyl ether. The white precipitate which formed wascollected on a filter. This product [1.4 g., m.p. 200°-203° C.(uncorr.)] was recrystallized from isopropyl acetate to yield 1.3 g. of3-(pivalyloxymethyl)-4-(pivaloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at200°-203° C. (uncorr.).

EXAMPLE 136

A. To 180 g. of isovaleric acid there was added 19 g. of sodiummethoxide in methyl alcohol. Methyl alcohol and methyl isovalerate wereremoved from the resulting reaction mixture by evaporation under reducedpressure on a steam bath. To the residue thus obtained there was added68.0 g. of 3-chloromethyl-4-acetoxyacetophenone, and the mixture washeated while allowing acetic acid formed in the reaction to distill off.The reaction mixture was concentrated on a rotary evaporator underreduced pressure. The resulting residue was slurried in diethyl etherand the ether layer was separated and washed three times with diluteaqueous sodium bicarbonate solution and once with water, dired overmagnesium sulfate, and concentrated under reduced pressure. The residuewas fractionally distilled under reduced pressure to yield 62 g. of3-(isovaleryloxymethyl)-3-(isovaleryloxy)acetophenone as a fractiondistilling at 158°-168° C. at 0.08-0.1 mm. Hg. pressure.

B. To 33.4 g. of 3-(isovaleryloxymethyl)-4-(isovaleryloxy)acetophenonein 200 ml. of chloroform there was added dropwise with stirring 5.2 ml.of bromine at 0° C. The reaction mixture was washed with dilute aqueoussodium bicarbonate solution, dried over magnesium sulfate, andconcentrated. The residue thus obtained, which contained3-(isovaleryloxymethyl)-4-(isovaleryloxy)-alpha-bromoacetophenone, wasadded with cooling to a solution of 7.3 g. of tert-butylamine and 10.1g. of triethylamine in 150 ml. of dimethyl sulfoxide. This reactionmixture was stirred at 15° C. for 30 minutes and then was poured intoice-water and extracted with diethyl ether. The ether extract was washedonce with water, dried over anhydrous calcium sulfate, and concentrated.The residue, which was crude3-(isovaleryloxymethyl)-4-(isovaleryloxy)phenyl tert-butylaminomethylketone, was reacted with methanesulfonic acid to yield 5.0 g. of3-(isovaleryloxymethyl)-4-(isovaleryloxy)phenyl tert-butylaminomethylketone methanesulfonate as a crystalline solid which melted at 190°-215°C. (uncorr.).

C. To a solution of 5.0 g. of3-(isovaleryloxymethyl)-4-(isovaleryloxy)phenyl tert-butylaminomethylketone methanesulfonate in 60 ml. of methyl alcohol at -10° C. there wasadded portionwise 0.6 g. of sodium borohydride. The reaction mixture wasstirred for 15 minutes at -5° to -10° C. and then was neutralized byaddition of acetic acid, and concentrated on a rotary evaporator. Thisresidue thus obtained was dissolved in 50 ml of cold water and thesolution was made slightly basic by addition of ammonium hydroxide andthereafter was extracted three times with diethyl ether. The etherextracts were combined, dired over anhydrous calcium sulfate, andconcentrated. The resulting gummy residue, which was crude3-(isovaleryloxymethyl)-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzylalcohol, was converted to 3.5 g. of3-(isovaleryloxymethyl)-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at125°-126° C. (uncorr.).

EXAMPLE 137

By interaction of 3-hydroxymethyl-4-hydroxyphenyl tert-butylaminomethylketone hydrochloride with two equivalents of p-toluyl chloride intrifluoroacetic acid there is obtained3-(p-toluyloxymethyl)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketonetrifluoroacetate. Conversion of this salt to the free base and reactingthe latter with methanesulfonic acid yields the correspondingmethanesulfonate salt which by reduction with sodium borohydride inanhydrous methyl alcohol is converted to3-(p-toluyloxymethyl)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate. Esterification of this alcohol by treatmentwith pivalyl chloride yields the methanesulfonate of3-(p-toluyloxymethyl)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylpivalate.

EXAMPLE 138

Using a procedure similar to that described above in Example 2A, 22.5 g.of 3,4-dihydroxyphenyl 1-(cyclopentylamino)propyl ketone hydrochloridewas reacted under an atmosphere of nitrogen with 13 g. of sodiummethoxide, the resulting sodium phenolate salt was reacted with 20 g. ofisovaleryl chloride, the ester-amine salt thus obtained was converted tothe ester-amine by treatment with ammonium hydroxide, and the freeester-amine was then treated with hydrochloric acid to yield 19.8 g. of3,4-bis(isovaleryloxy)phenyl 1-(cyclopentylamino)propyl ketonehydrochloride as a white crystalline solid which melted at 182°-184° C.(uncorr.). This salt (19 g.) was catalytically hydrogenated, using theprocedure described above in Example 30B, to yield 16.3 g. of3,4-bis(isovaleryloxy)-alpha-[1-(cyclopentylamino)propyl]benzyl alcoholhydrochloride as a white crystalline solid, m.p. 150° C. (uncorr.).

EXAMPLE 139

Using a procedure similar to that described above in Example 58A, 13 g.of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride wasreacted with 8 g. of sodium methoxide in 200 ml. ofN,N-dimethylformamide under an atmosphere of nitrogen and then 8 g. ofm-toluyl chloride was added to produce 3-hydroxy-4-(m-toluyloxy)phenyltert-butylaminomethyl ketone hydrochloride. This salt was converted tothe free base which was treated with acetic acid to yield 11.5 g. of theacetate salt, m.p. 170°-175° C. By treating a slurry of this salt in 100ml. of N,N-dimethylformamide with 40 g. of methanesulfonic acid therewas obtained 10.6 g. of the corresponding methanesulfonate salt,m.p. >250° C. (uncorr.). This methanesulfonate (10 g.) was catalyticallyhydrogenated, using a procedure similar to that described above inExample 30B, to yield 5.4 g. of3-hydroxy-4-(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 165°-168°C. (uncorr.).

EXAMPLE 140

By insteracting 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethylketone hydrochloride with 8.0 g. of 2,2-dimethylpentanoyl chloride in 30ml. of trifluoroacetic acid on a steam bath for 1 hour and treating theresulting product with ammonium hydroxide there was obtained3-hydroxy-4-(2,2-dimethylpentanoyloxy)phenyl tert-butylaminomethylketone. This product was converted to the acetate salt (10.5 g.) andthis salt was converted to the corresponding methanesulfonate salt [8.3g., m.p. 250° C. (dec.)(uncorr.)], by treatment with a slight excess ofmethanesulfonic acid. When this methanesulfonate (8.0 g.) wascatalytically hydrogenated in the presence of palladium-on-charcoalcatalyst, there was obtained 5.8 g. of3-hydroxy-4-(2,2-dimethylpentanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at128°-130° C. (uncorr.).

EXAMPLE 141

3,4-Dihydroxyphenyl 1-(tert-butylaminomethyl)ethyl ketone hydrochloride(8 g.) was reacted with 18 ml. of pivalyl chloride in 35 ml. oftrifluoroacetic acid, the resulting ester-amine salt was converted tothe ester-amine, and the ester-amine was treated with hydrochloric acidto yield 10.5 g. of 3,4-bis-(pivalyloxy)phenyl tert-butylaminomethylketone hydrochloride, m.p. 200°-202° C. (uncorr.). This ketone wascatalytically hydrogenated in the presence of palladium-on-charcoalcatalyst to yield3,4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride as a white crystalline solid which melted at 205°-207° C.(uncorr.).

EXAMPLE 142

Using a procedure similar to that described above in Example 58A, 26 g.of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride wasreacted with 16 g. of sodium methoxide in 300 ml. ofN,N-dimethylformamide under an atmosphere of nitrogen and then 17 g. ofp-anisoyl chloride was added to produce 3-hydroxy-4-(p-anisoyloxy)phenyltert-butylaminomethyl ketone hydrochloride. This salt was converted tothe free base which was treated with acetic acid to yield 35 g. of theacetic salt, m.p. 170°-175° C. (dec.)(uncorr.). By treating this salt in(dec.) (uncorr.), with concentrated hydrochloric acid there was obtained28 g. of the hydrochloride salt, m.p. >235° C. (dec.) (uncorr.). Whenthis hydrochloride is catalytically hydrogenated, using a proceduresimilar to that described above in Example 30B, there is obtained3-hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride.

EXAMPLE 143

By interaction of 22 g. of 3-hydroxy-4-(p-anisoyloxy)phenyltert-butylaminomethyl ketone hydrochloride with 20 ml. of benzoylchloride in 50 ml. of trifluoroacetic acid and treatment of theacylation product with ammonium hydroxide and then with hydrochloricacid there was obtained 14.3 g. of 3-benzoyloxy-4-(p-anisoyloxy)phenyltert-butylaminomethyl ketone hydrochloride, m.p. 212°-215° C. (uncorr.).Catalytic hydrogenation of this ketone (14.0 g.) inN,N-dimethylformamide in the presence of palladium-on-charcoal catalystyielded3-benzoyloxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride which was converted to 6.3 g. of the correspondingmethanesulfonate salt as a white crystalline solid, m.p. 173°-175° C.(uncorr.).

EXAMPLE 144

By interacting 20 g. of 3,4-dihydroxyphenyl1-(tert-butylaminomethyl)propyl ketone hydrochloride with 25 ml. ofp-toluyl chloride in 50 ml. of trifluoroacetic acid and treating theacylation product with ammonium hydroxide and then with hydrochloricacid there was obtained 31 g. of 3,4-bis-(p-toluyloxy)phenyl1-(tert-butylaminomethyl)propyl ketone hydrochloride, m.p. 115°-120° C.(dec.)(uncorr.). Catalytic hydrogenation of this ketone (30 g.) inN,N-dimethylformamide in the presence of palladium-on-charcoal catalystyielded 20 g. of crude product, m.p. 115°-118° C. (dec.)(uncorr.), whichwas recrystallized from 100 ml. of isopropyl alcohol to yield 12.5 g. of3,4-bis(p-toluyloxy)-alpha-[1-(tert-butylaminomethyl)propyl]benzylalcohol hydrochloride as a white crystalline solid which melted at228°-230° C. (uncorr.).

EXAMPLE 145

3-Hydroxy-4-(p-anisoyloxy)phenyl tert-butylaminomethyl ketonehydrochloride (15 g.) was reacted with 11 g. of p-anisoyl chloride in 50ml. of trifluoroacetic acid, the resulting ester-amine salt wasconverted to the ester-amine, and the ester-amine was then treated withmethanesulfonic acid to yield 9.7 g. of 3-hydroxy-4-(p-anisoyloxy)phenyltert-butylaminomethyl ketone methanesulfonate, m.p. >250° C. (uncorr.).This product (9.7 g.) was suspended in a mixture of 100 ml. of aceticacid and 50 ml. of acetyl chloride and heated under reflux for 1 hour,and from the resulting reaction mixture there was obtained 10.7 g. of3-acetoxy-4-(p-anisoyloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate, m.p. 150°-152° C. (uncorr.). This ketone (10.3 g.) wascatalytically hydrogenated in N,N-dimethylformamide in the presence ofpalladium-on-charcoal catalyst to yield 9.1 g. of3-acetoxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 172°-174°C. (uncorr.).

EXAMPLE 146

By interaction of 16.2 g. of 3,4-dihydroxyphenyl tert-butylaminomethylketone hydrochloride with 5.2 ml. of acetyl chloride in 140 ml. oftrifluoroacetic acid there was obtained 3-hydroxy-4-acetoxyphenyltertbutylaminomethyl ketone hydrochloride. Without isolation, thisproduct was treated with 21 ml. of p-toluyl chloride to yield 8.0 g. of3-(p-toluyloxy)-4-acetoxyphenyl tert-butylaminomethyl ketonehydrochloride, m.p. 244°-246° C. (dec.)(uncorr.). Using a proceduresimilar to that described above in Example 30C., this ketone (7.9 g.)was reduced in anhydrous methyl alcohol with 750 mg. of sodiumborohydride and the resulting product was treated with methanesulfonicacid to yield 5.8 g. of3-(p-toluyloxy)-4-acetoxy-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 184°-186°C. (uncorr.).

EXAMPLE 147

By interaction of 20 g. of 3,4-dihydroxyphenyl tert-butylaminomethylketone hydrochloride with 8 ml. of acetyl chloride in 150 ml. oftrifluoroacetic acid there was obtained 3-hydroxy-4-acetoxyphenyltert-butylaminomethyl ketone hydrochloride. Without isolation, thisproduct was reacted with 15 ml. of o-toluyl chloride to yield 23 g. of3-(o-toluyloxy)-4-acetoxyphenyl tert-butylaminomethyl ketonehydrochloride, m.p. 236°-237° C. (dec.)(uncorr.). This ketone (20.0 g.)was reduced in anhydrous methyl alcohol with 1.35 g. of sodiumborohydride and the product was treated with methanesulfonic acid toyield 8.9 g. of3-(o-toluyloxy)-4-acetoxy-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white crystalline solid which melted at 190°-192°C. (uncorr.).

EXAMPLE 148

To a stirred solution of 20.0 g. of 3,4-dihydroxyphenyltert-butylaminomethyl ketone hydrochloride in 140 ml. of trifluoroaceticacid there was gradually added, over a 21/2 hour period, 7.5 ml. ofacetyl chloride. Stirring was continued for a further period of 2 hours,19.0 g. of 1-adamantanecarbonyl chloride was then added in a singleportion, and the reaction mixture was stirred for 21/2 hours at roomtemperature and finally one-half hour at 40° C. The reaction product wasisolated and treated with methanesulfonic acid to yield 19.2 g. of3-(1-adamantanecarbonyloxy)-4-acetoxyphenyl tert-butylaminomethyl ketonemethanesulfonate as a white crystalline solid. This ketone (18.5 g.) wascatalytically hydrogenated in N,N-dimethylformamide in the presence ofpalladium-on-charcoal catalyst to yield 7.4 g. of3-(1-adamantanecarbonyloxy)-4-acetoxy-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at203°-204° C. (uncorr.).

EXAMPLE 149

By interaction of 3,4-dihydroxyphenyl tert-butylaminomethyl ketonehydrochloride with 7.5 ml. of acetyl chloride in 150 ml. oftrifluoroacetic acid there was obtained 3-hydroxy-4-acetoxyphenyltert-butylaminomethyl ketone hydrochloride. Without isolation, thisproduct was reacted with 15 ml. of p-anisoyl chloride and the acylationproduct was treated with methanesulfonic acid to yield 19.8 g. of3-(p-anisoyloxy)-4-acetoxyphenyl tert-butylaminomethyl ketonemethanesulfonate as a white crystalline solid. [The correspondinghydrochloride melted at 235°-237° C. (uncorr.)] This product (19.5 g.)was catalytically hydrogenated in N,N-dimethylformamide in the presenceof palladium-on-charcoal catalyst to yield 7.2 g. of3-(p-anisoyloxy)-4-acetoxy-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate as a white solid which melted at 181°-182° C.(dec.)(uncorr.).

EXAMPLE 150

A. To a solution of 3-(acetoxymethyl)-4-acetoxyacetophenone in 150 ml.of N,N-dimethylformamide there was added, while stirring at roomtemperature, 14.0 g. of trans-2-phenylcyclopropylamine. (In another run,benzylamine was substituted for the trans-2-phenylcyclopropylamine withequivalent results). After stirring the reaction mixture for 2 hours itwas partitioned between ethyl acetate and water and the desired3-(acetoxymethyl)-4-hydroxyacetophenone was isolated in crude form fromethyl acetate solution as a pale yellow oil which weighed 38 g. [Whenpurified, this compound was a white crystalline solid, m.p. 108°-109° C.(uncorr.)]. This oil was dissolved in a mixture of 100 ml. of diethylether and 100 ml. of benzene and while stirring the solution 15 ml. oftriethylamine was added followed by dropwise addition of 19.2 g. ofp-toluyl chloride. The resulting reaction mixture was stirred at roomtemperature over night and then by extraction with diethyl ether andpurification there was obtained 20.2 g. of3-acetoxymethyl-4-(p-toluyloxy)acetophenone as a white crystallinesolid, m.p. 85°-89° C. (uncorr.). This product (20 g.) was dissolved in180 ml. of chloroform, and a trace of hydrobromic acid was addedfollowed by addition, at 5° C. with stirring, of a solution of 10.0 g.of bromine in 40 ml. of chloroform. Cold aqueous sodium bicarbonatesolution was added to the reaction mixture, and the chloroform layer wasseparated, dried, and evaporated under reduced pressure to yield a paleyellow oil which crystallized. This solid was washed with cold diethylether. The off-white solid thus obtained, which weighed 23.8 g., was3-acetoxymethyl-4-(p-toluyloxy)-alpha-bromoacetophenone, m.p. 75°-77° C.(uncorr.). A solution of 11.8 g. of this product in 30 ml. ofN,N-dimethylformamide was added dropwise over a period of forty minutesto a stirred solution of 9.5 g. of tert-butylamine in 100 ml. ofN,N-dimethylformamide at -50° C. The reaction mixture was stirred fortwenty minutes, allowed to warm to 0° C., and diluted with 400 ml. ofdiethyl ether, and the reaction product was partitioned between diethylether and water. The resulting ether extract was dried, ethanolichydrogen chloride was added, and the mixture was cooled. The solid whichseparated from solution was collected on a filter. There was thusobtained 10.0 g. of 3-acetoxymethyl-4-(p-toluyloxy)phenyltert-butylaminomethyl ketone hydrochloride as a white crystalline solidwhich melted at 235°-245° C. (dec.)(uncorr.).

B. To 15.2 g. of 3-acetoxymethyl-4-(p-toluyloxy)phenyltert-butylaminomethyl ketone hydrochloride in 150 ml. of anhydrousmethyl alcohol, cooled to 0° C. there was added 700 mg. of sodiumborohydride. After 10 minutes, several drops of acetic acid were addedto neutralize the reaction solution which was then evaporated todryness. The reaction product was extracted into a mixture of diethylether and methylene dichloride and from this extract there was recovered7.5 g. of3-acetoxymethyl-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at163°-165° C. (uncorr.).

EXAMPLE 151

A. Proceeding in a manner similar to that described above in part A ofExample 150: 40 g. of 3-(acetoxymethyl)-4-hydroxyacetophenone wasreacted with 21 g. of p-anisoyl chloride in methylene chloride in thepresence of 18 ml. of triethylamine to yield 33.6 g. of3-acetoxymethyl)-4-(p-anisoyloxy)acetophenone as a white crystallinesolid; this product (33 g.) was brominated in chloroform by treatmentwith 16 g. of bromine to yield 34.8 g. of3-(acetoxymethyl)-4-(p-anisoyloxy)-alpha-bromoacetophenone as a whitecrystalline solid, m.p. 90°-91° C. (uncorr.); and reaction of this bromoketone (17.8 g.) with 20 ml. of tert-butylamine in N,N-dimethylformamideat -55° C. yielded 3-(acetoxymethyl)-4-(p-anisoyloxy)phenyltert-butylaminomethyl ketone which was treated with ethanolic hydrogenchloride to yield 30.2 g. of 3-(acetoxymethyl)-4-(p-anisoyloxy)phenyltert-butylaminomethyl ketone hydrochloride as a white crystalline solidwhich melted at 220°-228° C. (dec.) (uncorr.).

B. To a slurry of 29.9 g. of 3-(acetoxymethyl)-4-(p-anisoyloxy)phenyltert-butylaminomethyl ketone hydrochloride in 200 ml. of anhydrousmethyl alcohol at 0° C. there was added, portionwise over a period offifteen minutes, 1.25 g. of sodium borohydride. Then after 10 minutes, afew ml. of acetic acid were added and the reaction mixture wasevaporated to dryness. The reaction product was extracted into methylenechloride and from this extract there was recovered3-(acetoxymethyl)-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol which was converted to 15.3 g. of its methanesulfonate salt, awhite crystalline solid which melted at 181°-182° C. (uncorr.).

EXAMPLE 152

A. Proceeding in a manner similar to that described above in Example150: 15.0 g. of 3-(acetoxymethyl)-4-hydroxyacetophenone was reacted with14.3 g. of 1-adamantanecarbonyl chloride in methylene chloride in thepresence of 10.5 g. of triethylamine to yield 30.0 g. of curde3-(acetoxymethyl)-4-(1-adamantanecarbonyloxy)acetophenone as a nearlycolorless oil; this product (26 g.) was brominated in chloroform bytreatment with 11.2 g. of bromine to yield 34 g. of crude3-(acetoxymethyl)-4-(1-adamantanecarbonyloxy)-alpha-bromoacetophenone;and this bromo ketone (30 g.) was reacted with 33 ml. of tert-butylaminein N,N-dimethylformamide at -60° C. to yield 20.0 g. of3-(acetoxymethyl)-4-(1-adamantanecarbonyloxy)phenyltert-butylaminomethyl ketone hydrochloride as a white crystalline solid,m.p. 240°-241° C. (dec.)(uncorr.).

B. Using a procedure similar to that described above in part B ofExample 151, 20 g. of3-(acetoxymethyl)-4-(1-adamantanecarbonyloxy)phenyltert-butylaminomethyl ketone hydrochloride was reduced in anhydrousmethyl alcohol with 1.0 g. of sodium borohydride and the reductionproduct was treated with methanesulfonic acid to yield 9.3 g. of3-(acetoxymethyl)-4-(1-adamantanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at183°-185° C. (dec.)(uncorr.).

EXAMPLE 153

A. Proceeding in a manner similar to that described above in Example150: 15.0 g. of 3-(acetoxymethyl)-4-hydroxyacetophenone was reacted witho-toluyl chloride in methylene chloride in the presence of 10.5 ml. oftriethylamine to yield 24 g. of3-(acetoxymethyl)-4-(m-toluyloxy)acetophenone as a white crystallinesolid; this product (23 g.) was brominated in chloroform by treatmentwith 11.2 g. of bromine to yield 30 g. of3-(acetoxymethoxy)-4-(m-toluyloxy)-alpha-bromoacetophenone as a paleyellow oil; and this bromo ketone c28 g.) was reacted with 33 ml. oftriethylamine in N,N-dimethylformamide to yield3-(acetoxymethyl)-4-(o-toluyloxy)phenyl tert-butylaminomethyl ketone,m.p. 235°-242° C. (dec.)(uncorr.), which was treated with ethanolichydrogen chloride to yield 22 g. of3-(acetoxymethyl)-4-(o-toluyloxy)phenyl tert-butylaminomethyl ketonehydrochloride as a white crystalline solid.

B. Proceeding in a manner similar to that described above in part B ofExample 151, 22 g. of 3-(acetoxymethyl)-4-o-toluyloxy)phenyltert-butylaminomethyl ketone hydrochloride was reduced in anhydrousmethyl alcohol with 1.13 g. of sodium borohydride and the reductionproduct was treated with methanesulfonic acid to yield3-(acetoxymethyl)-4-(o-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate as a white solid which melted at 116°-118° C.(uncorr.).

EXAMPLE 154

When 3-(pivalyloxymethyl)-4-(pivalyloxy)acetophenone is selectivelyde-acylated at the 4-position by treatment with benzylamine by theprocedure described above in part A of Example 150, there is produced3-(pivalyloxymethyl)-4-hydroxyacetophenone. By treating this productwith one equivalent of sodium methoxide and reacting the resultingsodium phenolate with m-toluyl chloride, using a procedure similar tothat described above in Example 2A, there is obtained3-(pivalyloxymethyl)-4-(m-toluyloxy)acetophenone. Using a proceduresimilar to that described above in Example 135C, bromination of thisproduct yields3-(pivalyloxymethyl)-4-(m-toluyloxy)-alpha-bromoacetophenone whichreacts with tert-butylamine to yield3-(pivalyloxymethyl)-4-(m-toluyloxy)phenyl tert-butylaminomethyl ketone.Conversion of this ester-ketone to the methanesulfonate and catalytichydrogenation in the presence of palladium-on-charcoal hydrogenationcatalyst yields3-(pivalyloxymethyl)-4-(m-toluyloxy)alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate. Reaction of this compound with p-toluylchloride yields the methanesulfonate of3-(pivalyloxymethyl)-4-(m-toluyloxy)alpha-(tert-butylaminomethyl)benzylp-toluate. Treatment of this product with benzylamine inN,N-dimethylformamide at room temperature for several hours yields3-(pivalyloxymethyl)-4-hydroxy-alpha-(tert-butylaminomethyl)benzylp-toluate.

EXAMPLE 155

By reacting 3-hydroxymethyl-4-hydroxyacetophenone [m.p. 124°-125° C.(uncorr.); obtained by hydrolysis of the corresponding diacetate,3-(acetoxymethyl)-4-acetoxyacetophenone, with dilute aqueoushydrochloric acid] with two molecular equivalents of p-toluyl chloridein trifluoroacetic acid there is produced3-(p-toluyloxymethyl)-4-(p-toluyloxy)acetophenone. Proceeding asdescribed above in Example 154, but using as the starting material3-(p-toluyloxymethyl)-4-(p-toluyloxy)acetophenone instead of3-(pivalyloxymethyl)-4-(pivalyloxy)acetoxphenon, there are obtainedsuccessively the products:

3-(p-toluyloxymethyl)-4-hydroxyacetophenone;

3-(p-toluyloxymethyl)-4-(m-toluyloxy)acetophenone;

3-(p-toluyloxymethyl)-4-(m-toluyloxy)-alpha-bromoacetophenone;

3-(toluyloxymethyl)-4-(m-toluyloxy)phenyl tert-butylaminomethyl ketoneand its methanesulfonate;

3-(p-toluyloxymethyl)-4-(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol methanesulfonate;

the methanesulfonate of3-(p-toluyloxymethyl)-4-(m-toluyloxy)-alpha-(tert-butylaminomethyl)-benzylp-toluate; and

3-(p-toluyloxymethyl)-4-hydroxy-alpha-(tert-butylaminomethyl)benzylp-toluate.

The following are further illustrative examples of the esters ofFormulas I and II which are obtained in accordance with the hereinabovedescribed procuedures:3,4-bis(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl pivalate;3-(pivalyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylisovalerate; 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylp-toluate;3,4-bis(2-methylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzylcyclopropanecarboxylate;3,4-bis(octadecanoyloxy)-alpha-(tert-butylaminomethyl)benzyl3,6-octadienoate;3-hydroxy-4-(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzylphenoxyacetate;3-hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzylnicotinate; 3,4-bis(p-toluyloxy)-alpha-(isopropylaminomethyl)benzylpropionate;3,4-bis(2,4-dimethylbenzoyloxy)-alpha-(methylaminomethyl)benzyl-2-naphthalenecarboxylate;3,4-bis(p-toluyloxy)-alpha-(aminomethyl)benzyl cyclohexaneacetate;3,4-bis-(p-toluyloxy)-alpha[1-(isopropylamino)-2-methylpropyl]benzylp-acetamidophenylacetate;3,4-bis(isovaleryloxy)-alpha-[1-(tert-butylamino)butyl]benzyl stearate;3,4-bis(m-chlorobenzoyloxy)-alpha-[1-(cyclopropylamino)-propyl]benzylp-trifluoromethylbenzoate;3-hydroxy-4-(decanoyloxy)-alpha-[1-(cyclohexylamino)ethyl]benzyl2,3,5-trifluorobenzoate;3-hydroxy-4-(2,5-hexadienoyloxy)-alpha-[1-(tert-butylamino)-2-methylpropyl]benzylalcohol; 3,4-bis(p-toluyloxy)-alpha-[1-(cyclohexylamino)butyl]benzylalcohol;3-(p-toluyloxymethyl)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol;3-(p-toluyloxymethyl)-4-hydroxy-alpha-(tert-butylaminomethyl)benzylalcohol;3-(p-toluyloxymethyl)-4-(m-toluyloxy)-alpha-[1-(tert-butylamino)ethyl]benzylalcohol;3-(isonicotinoyloxymethyl)-4-(crotonoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol;3-(cyclobutanecarbonyloxymethyl)-4-(phenoxyacetoxy)-alpha-(aminomethyl)benzylalcohol; 3-(o-toluyloxymethyl)-4-(benzoyloxy)-alpha-(1-aminoethyl)benzylalcohol;3-(p-toluyloxymethyl)-4-(p-toluyloxy)-alpha-(cyclopropylaminomethyl)benzylalcohol;3-(dodecanoyloxymethyl)-4-(p-diethylaminobenzoyloxy)-alpha-(1-aminopropyl)benzylalcohol;3-(p-bromobenzoyloxymethyl)-4-(cyclopentanecarbonyloxy)-alpha-(isopropylaminomethyl)benzylalcohol;3-(benzoyloxymethyl)-4-(cyclobutaneacetoxy)-alpha-[1-(ethylamino)ethyl]benzylalcohol;3-(phenoxyacetoxymethyl)-4-hydroxy-alpha-(tert-butylaminomethyl)benzylalcohol;3-(3-phenylpropionyloxymethyl)-4-hydroxy-alpha-[1-(tert-butylamino)-2-methylpropylbenzylalcohol;3-(m-chlorobenzoyloxymethyl)-4-(pivalyloxy)-alpha-(cyclopropylaminomethyl)benzylalcohol;3-(3,4-dimethylbenzoyloxymethyl)-4-(3,4-dimethylbenzoyloxy)-alpha-(cyclohexylaminomethyl)-benzylalcohol;3-(3,4,5-trimethoxybenzoyloxymethyl)-4-(acetoxy)-alpha-[1-(cyclopentylamino)propylbenzylalcohol;3-(2-bromo-4-methoxybenzoyloxymethyl)-4-(cyclohexylacetoxy)-alpha-[1-(tert-butylamino)butyl]benzylalcohol;3-(1-naphthalenecarbonyloxymethyl)-4-hydroxy-alpha-(ethylaminomethyl)benzylphenylacetate;3-(p-anisoyloxymethyl)-4-(2,2-dimethylpentanoyloxy)-alpha-(isopropylaminomethyl)benzylacetate;3-(p-toluyloxymethyl)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylstearate;3-(phenoxyacetoxymethyl)-4-(cyclopentanecarbonyloxy)-alpha-[1-(tert-butylamino)propyl]benzyl2-methylcyclopropanecarboxylate;3-(2,4-dimethylbenzoyloxymethyl)-4-(3,4-dimethylbenzoyloxy)-alpha-(aminomethyl)benzyl2,5-hexadienoate;3-(3,3-dimethylbutanoyloxymethyl)-4-(cycloheptanecarbonyloxy)-alpha-[1-(methylamino)ethyl]benzyl-m-toluate;3-(2-adamantanecarbonyloxy)-4-(1-adamantanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol;3-(1-adamantanecarbonyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol;3-pivalyloxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol;3-benzoyloxymethyl-4-(2-adamantanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol;3-(1-adamantanecarbonyloxymethyl)-4-(m-toluyloxy)-[alpha-(1-tert-butylamino)ethyl]benzylalcohol;3-cyclohexanecarbonyloxy-4-(1-adamantanecarbonyloxy)-alpha-[1-(isopropylamino)-propyl]benzylalcohol;3-cyclobutanecarbonyloxymethyl-4-(p-trifluoromethylbenzoyloxy)-alpha-(1-aminoethyl)benzylalcohol;3,4-bis(1-adamantanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol; 3,4-bis(p-toluyloxy)-alpha-(butylaminomethyl)benzyl alcohol;3,4-bis(p-anisoyloxy)-alpha-(propylaminomethyl)benzyl alcohol;3,4-bis-(3,4-diethoxybenzoyloxy)-alpha-(aminomthyl)benzyl alcohol;3-(p-toluyloxy)-4-(p-anisoyloxy)-alpha-(cyclobutylaminomethyl)benzylalcohol;3-(p-acetamidobenzoyloxy)-4-(1-adamantanecarbonyloxy)-alpha-(isobutylaminomethyl)benzylalcohol;3-nicotinoyloxymethyl-4-pivalyloxy-alpha-(tert-butylaminomethyl)benzylalcohol;3-(3,3-dimethylbutanecarbonyloxymethyl)-4-(p-toluyloxy)-alpha-(methylaminomethyl)benzylalcohol;3-benzoyloxymethyl-4-benzoyloxy-alpha-(tert-butylaminomethyl)benzylalcohol; and3-pivalyloxy-4-(2-naphthalenecarbonyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol.

The esters of Formula I and Formula II prepared in accordance with thisinvention have been demonstrated to have useful sympathomimetic activityof long duration; and the hereinabove-indicated preferred species arefurther desirably characterized by a low cardiovascular stimulatingeffect, as can be seen from the results described below. The referencecompounds referred to in these results are identified as follows:

I. 3,4-Dihydroxy-alpha-(tert-butylaminomethyl)benzyl alcohol

II. 3,4-Dihydroxy-alpha-(isopropylaminomethyl)benzyl alcohol

III. 3-Hydroxymethyl-4-hydroxy-alpha-(tert-butylaminomethyl)benzylalcohol

IV. 3,4-Dihydroxy-alpha-[1-(isopropylamino)-propyl]benzyl alcohol

V. 3,4-Dihydroxy-alpha-(methylaminomethyl)benzyl alcohol

Bronchodilator activity was tested in anesthetized dogs (Test Method I)and in vitro on the perfused guinea pig lung (Test Method II), using thefollowing pharmacological test procedures

Test Method I

Male and female dogs weighing 9-18 kg. each were anesthetized withpentobarbital sodium (30 mg./kg. i.v.). Each animal, with thorax openedat the midsternum, was maintained under artificial ventilation using aconstant volume pump (250 ml./stroke; 10 to 12 strokes per minute)attached to the tracheal cannula. The flow of air was controlled by aglass or plastic valve which closed and opened respectively on inflowand outflow of the air to and from the tracheal cannula.Bronchoconstriction and/or bronchodilatation were measured from changesin the basal airway pressure reflected by a transducer attached to thesidearm of the cannula relayed to a polygraph.

Control bronchoconstrictions were induced by intravenous injections ofcarbachol (choline chloride carbamate) in doses ranging from 4 to 6micrograms per kilogram or histamine diphosphate in doses ranging from35 to 45 micrograms per kilogram. In the majority of test animals, theabove doses of constrictor agents produced a 100-200 percent increase inthe normal airway pressure or amplitude.

Solutions of the test compounds were prepared in distilled water or insaline (for infusion). Addition of a stabilizing agent,ethylenediaminetetraacetic acid, the solutions of the referencecompounds I, II, IV, and V was required to stabilize them. Thesesolutions were then tested for bronchodilator activity in three ways,viz. (1) by mixing a graded dose of test compound with the constant doesof carbachol or histamine in a syringe and injecting the mixture intothe femoral vein of the dog, (2) by producing the bronchoconstrictionfirst and injecting the test compound at the time of maximumconstriction, and (3) by injecting the test compound first followed bycarbachol or histamine in 1-10 minutes. Injections were repeated at20-30 minutes. Bronchodilator values were obtained by measuring theareas under the response polygraph tracings (the first 5 munite period)of carbachol or histamine controls and of the experimentals using aplanimeter. Decrease in the area thus measured was expressed as apercent bronchodilatation in reference to the area of control carbacholor histamine constriction. The mean bronchodilatations (the reductionsin constrictions) were plotted against the doses administered and themean effective dose (ED₅₀) was estimated in micrograms/kilogram from thedoes-response curves. Blood pressure recording was taken from thefemoral artery using an arterial transducer relayed to a polygraph.

In intratracheal studies, an animal preparation identical with thatdescribed above was used. A modified "aerosol actuator" was attachedbetween the valve and the tracheal cannula and the aerosol medicationwas delivered directly into the tracheal passage during the inflow ofair. Commencing five minutes after medication, the degree and durationof bronchodilator effect was tested at intervals of 30-60 minutes untila full or near-full recovery (a degree of constriction approaching thepremedication control) was observed.

In intraduodenal studies, in the dog prepared for bronchodilationmeasurements, the duodenal segment of the small intestine was madeeasily accessible through a small mid-line incision in the abdomen. Thetest solution was injected into the duodenum using a fine needle.Commencing 5 minutes after medication, the degree and duration ofbronchodilation were tested by injecting a control dose of carbachol orhistamine at intervals of 30-60 minutes until the recovery ornear-recovery was apparent. In some dogs showing an early recovery, areference drug was also tested in the same dog 1.5-2 hours after thefirst medicine.

Representative results which were obtained in the anesthetized dog areset forth below.

    __________________________________________________________________________    Intravenous Activity                                                          Bronchodilatation in Percent                                                  Minutes After Medication                                                      Cpd. of                                                                            No. of                                                                            Dose                                                                 Ex. No.                                                                            Dogs                                                                              mcg/kg                                                                             5    30 60 120  180                                                                              240                                                                              270                                                                              300                                    __________________________________________________________________________    30   3   70   54   63 61 52      37                                                3   140  65   76 69 55   62    42                                             3   280  83   88 75 72   64 50                                                         2 min.                                                          4    1   5.5  48   5  0                                                                     2 min.                                                          15   1   1.2  20   27 8  0                                                         1   3.0  36      31 26   20                                                            2 min.                                                          13   1   2.8  52   48 0                                                            1   5.6  69   34 10                                                      7    3-4 28.5 28   32 24 24   22 23                                                3-4 114  52   42 33 25   19                                                   3-4 228  98   77 68 56   50 44                                           5    2   2.8  14                                                                   6   5.6  53   27 26                                                           2   11.2 57   30 4                                                            1   22.4      81 62 62   15 0                                                 1   112.0                                                                              100  92 59 13                                                                 1-2 min.                                                        3    4-8 0.55 32                                                                   4-8 1.1  54                                                                   4-8 2.2  74                                                                            1-2 min.                                                        111      9.5       8  15                                                               9.5  0    0  0                                                                47.5 0    0  0                                                                47.5 35   18 22                                                               47.5 12   0  0  0                                                             95   34   36 39 32   48 41    50                                              95   45   23 0                                                                190  27   11 18 31                                                            190  38   41 25 38   35 41    25                                              380  33   53 38 55   38 33                                                    380  44   50 63 56   50 10                                           118  4   14   68   61 35 7                                                         4   56   100  60 45 12                                                                 1-2 min.                                                        126      147       27 15                                                               294  13   8  17                                                               1176 100  47 20                                                      132      76   0    12 0  0                                                             76   12   0                                                                   76   38   21 4  5                                                             152  67   -- 71 52   43 0     0                                               152  66   75 62                                                               152  80   67 64                                                               304  100  67 34 8    0  0     0                                               304  100  69 60 51   23 14                                           134      75   25   21 5  0    0                                                        150  54   -- 52 35   20 0                                                     150  61   58 36 28                                                            300  --   30 22 0    0                                                        300  47   49 37 16   0                                                        300  59   79 70 54   46 36                                           135  3   5    18   32 36 26                                                        3   20   30   49 50 56   50 45    36                                          3   80   38   64 62 66   62 56    49                                     136      5    0    0  47 29                                                            5    49   63 63 59   53 46    46                                          1   20   36   53 57 40   12 7     12                                          1   100  82   80 70 60   42       32                                     112  3   68   38   43 27                                                           2   137  80   60 50 37   8                                                    2   274  80   74 57 54   33 38 25                                        138  1   30   38   0                                                               1   240  49   62 42 46                                                   139  1   25   81   22 24 0                                                         1   100  74   63 22 25   9        10                                     145  7   5    65   30 24 22                                                        4   20   87   45 35 27                                                        4   40   98   70 68 42   38 24                                           146  1   1.2  31   38 44 --   20 20                                                1   6.0  66   57 63                                                      147  2   1.2  36   3  0                                                            1   6.0  77   9  0                                                            1   25.0 100  32 12 4                                                    148  1   1.3  21   1  10 16                                                        3   6.5  47   30 23 15   13                                                   3   32.5 95   66 54 39   28 14                                           149  1   0.5  54   19 19                                                           1   6.0  100  32 24                                                      150  3   8    42   37 44 44   32 20                                                3   32   64   66 54 40   30 0                                                 1   128  85   87 67 60   52 24                                           151  1   8    43   33 50 43   30    20                                             3   32   54   46 41 54   21 18                                                3   128  85   81 81 73   69 64 52                                        152  1   8    44   39 50 33   39 39 0                                              1   32   77   78 75 70   63 52 45                                             1   128  97   92 93 87   89 88 82                                        Ref.          1-2 min.                                                        Cpd. I                                                                             4-8 0.17 22                                                                   4-8 0.35 57                                                              Ref.          1-2 min.                                                        Cpd. II                                                                            4-8 0.3  23                                                                   4-8 0.6  35                                                                   4-8 1.2  55                                                              Ref.                                                                          Cpd. III                                                                           3   0.25 18   0                                                               3   1    31   14 3                                                            5   4    65   24 18 0                                                    Ref.                                                                          Cpd. IV                                                                            1   2    32   0                                                               3   4    72   31 19                                                           2   8    74   13 13                                                      Cpd. of  Dose                                                                 Ex. No.  mcg/kg                                                                             1-2  10 30 Minutes                                              Ref.     4    0    0                                                          Cpd. V   8    36   0                                                                   8    33      0                                                                8    0    0                                                                   16   69      5                                                                16   15                                                                       64   29      0                                                       __________________________________________________________________________

    __________________________________________________________________________    Intratracheal Activity (Aerosol Application)                                           No. of                                                                        Aerosol                                                                       Actuations                                                           Cpd. of                                                                            No. of                                                                            (dose in   Minutes                                                   Ex. No.                                                                            Dogs                                                                              γ/act.)                                                                            5    30 60 90 120 150                                                                              180                                                                              240                               __________________________________________________________________________    1    5  1-(375)     1-2 min.                                                                      68-90                                                                              24-                                                                              10-                                                                              0-                                                                      68 58 40                                             3    8  1-(400)                                                                              1-2 min.                                                                           60-100                                                                             37-                                                                              10-                                                                              10-                                                                              0-                                                                   67 55 30 20                                          5    3  1-(400)     2 min.                                                                        30-75                                                                              30-                                                                              30    13                                                                   58                                                        6  2-(400)     1-2 min.                                                                      32-80                                                                              41-                                                                              24-   15-                                                                  87 87    80(b)                                       30   3  1-(269)     3 min.                                                                        35   34 36    31(a)                                            3  2-(269)     1-2 min.                                                                      41      45    40                                               3  4-(260)     1-2 min.                                                                      54   65 63    55                                          112     1-(282)                                                                              (C)  50   41 38    19     0  0                                         1-(282)                                                                              (C)  53   23 30    30     43 37                                        1-(282)                                                                              (H)  44   28 47    35  33                                              1-(282)                                                                              (C)  59   39 37    20     0  0                                         1-(282)                                                                              (H)  50   33 26    29     21 21                                        2-(282)                                                                              (H)  17   20 13    3      2  0                                         2-(282)                                                                              (C)  36   71 48    26     0  0                                         2-(282)                                                                              (C)  73   68 60    35     13 13                                        4-(282)                                                                              (H)  53   56 50    46     51 49                                        4-(282)                                                                              (H)  53   37 46    57     54 54                                        4-(282)                                                                              (H)  48   20 12    0         0                                 116     2-(296)                                                                              (H)  7    0  27    20     0  0                                         2-(296)                                                                              (H)  32   37 40    29     14 0                                 118  5  2-(266)     60   44 36    32                                               4  4-(266)     56   43 34    21                                          120     1-(200)                                                                              (C)  32   32 0                                                         1-(200)                                                                              (C)  33   23                                                           2-(200)                                                                              (H)  52   40 44    4      0                                            2-(200)                                                                              (C)  100  87 56    0      0                                            2-(200)                                                                              (C)  56   39 53    0      0                                            4-(200)                                                                              (C)  100  100                                                                              70    80     50                                           4-(200)                                                                              (C)  71   74 60    34     20 0                                 123     1-(275)                                                                              (H)  19   26 26 4  7                                                   1-(275)                                                                              (H)  17   55 17    24  50 10 40                                        2-(275)                                                                              (C)  73   38 13    0      0                                            2-(275)                                                                              (C)  15   4  0                                                         2-(275)                                                                              (H)  48   49 58    36     64 48                                        4-(275)                                                                              (H)  61   56 72    37     22 0                                         4-(275)                                                                              (C)  60   55 59    36     29 25                                139  2  1-(222)                                                                              (H)  43   33 19    15                                               3  2-(222)                                                                              (H)(C)                                                                             71   53 33    13                                               3  4-(222)                                                                              (H)(C)                                                                             83   64 52    23  18                                      145  5  1-(250)                                                                              (H)  48   45 37    38  32    33                                     5  2-(250)                                                                              (H)  73   58 45    49  33    35                                     3  4-(250)                                                                              (H)  88   70 62    55  54    50                                Ref.                                                                          Cpd. I                                                                             8  1-(300)     38-98                                                                              0- 0-                                                                         67 18                                                Ref.                                                                          Cpd. II                                                                            2  1-(125)     60-70                                                                              0                                                         4  2-(125)     57-80                                                                              0-                                                                            30                                                   __________________________________________________________________________     Notes                                                                         (a) after 180 minutes the values were 29,36, and 32, respectively: and        after 240 minutes the values were 11, 40, and 43, respectively.               (b) after 180 minutes the values were 12 and 12-78, respectively: and         after 240 minutes (for 2 dogs) the value for the two dose level was 18-77

    __________________________________________________________________________    Intraduodenal Activity                                                        Bronchodilation in Percent                                                    Minutes after Medication                                                               Dose                                                                 Cpd. of                                                                            No. of                                                                            (salt)                                                               Ex. No.                                                                            Dogs                                                                              mcg/kg                                                                             5  10 30 60 120                                                                              180                                                                              240                                                                              300                                        __________________________________________________________________________    30   4   70      38*                                                                              45 42 42*                                                                              42 25*                                                4   140     30 35 36 45 40 47                                                 4   280     75 71 64*                                                                              56 50 45*                                                                              37*                                        135  3   25   18    -- 56 55 45 34 27                                              3   50   31    56 74 73 64 51 37                                          (36 after 6 hrs.)                                                            127      450        0  0                                                               450  16 16 16 0                                                       (0 after 90 min.)                                                            112  1   68   50 0                                                                 1   136  42 59 67 53 0                                                   145  4   20   33    32 32 33 29 25 23                                              7   80   53    48 45 49 32 30                                                 6   160  82    81 81 63 48 32 37                                         146  2   38   60    39 39 26 33 24 13                                         149  1   5    0     7  13 5  9  0                                                  1   40   78    52 44 31 -- 35 35                                              1   160  72    61 56 11 22 23                                            150  1   32   12    12 12 0  0                                                     1   128  68    68 61 61 45 39                                            151  1   32   24    40 36 36 28    20                                              1   128  54    63 66 66 66    43                                         152  1   32   6     6  17 48 45 45 21                                              1   128  6     43 59 51 65 59 54                                         Ref. 3   35      34 41 44 27 3                                                Cpd. I                                                                             1   70      40 60 35 30 -- 0                                                  3   280     66 59 46 54 30                                               Ref. 3   30      9  5  0                                                      Cpd. II                                                                            5   120     28 5  19                                                     Ref. 3   25      45    51 43 0                                                Cpd. III                                                                           3   50      13 42 56 71 53 34 6                                          __________________________________________________________________________     *Mean of 3 dogs                                                          

Bronchodilator Test Method II

In this method bronchodilator activity in vitro was determined bytesting the effect of graded doses of the test compounds on guinea pigbronchioles constricted by carbachol, using the technique reported bySollman and von Oettingen, Proc. Soc, Exp. Biol. Med., 25,692 (1928) asmodified by Tainter, Pedden, and James, J. Pharm. Exp. Ther., 51, 371(1934) and by Luduena, von Euler, Tullar, and Lands, Arch. intern.Pharmacol., III, 392 (1957).

Representative results which were obtained in this test are set forth inthe following table.

    ______________________________________                                        Bronchodilator Action                                                                   ED.sub.50                                                                             Dose            Duration                                    Cpd. of   mcg     mcg      No. of (min)                                       Ex. No.   (base)  (base)   Lungs  Mean                                        ______________________________________                                        Ref. Cpd. I                                                                             0.18    0.32     6      5 ± 1.4                                  Ref. Cpd. II      0.75     17      5                                          1         0.23    0.5      6      9 ± 1.0                                  2         0.28    0.5      9      9 ± 1.1                                  3         0.6     1.2      6      18 ± 4                                   5         0.94    2        5      18 ± 4.2                                 4         0.45    1        7      20 ± 3                                   13        0.45    0.79     6      15 ± 1.7                                 6         1.3     3.2      6      43 ± 3.7                                 71        0.63    2        5       26                                         7         23      32       6      85 ± 17                                  15        1.3     3.2      6      53 ± 7                                   29        1.1     3.2      7      34 ± 6.4                                 30        3.2     10       8      60 ± 9.6                                 33        6.9     10       5      32 ± 5                                   58        1.4     2.4      6      12 ± 2.5                                 59        1.2     3.2      6      25 ± 5.6                                 89        6.4     15       5      125 ± 31                                 138       0.46    1.5      6      25.4 ± 3.5                               141       13.6    25       6      17 ± 6.7                                 112       4.4     10       6      104.1 ± 34.9                             139       2.64    6        6      29.8 ± 4.4                               143*      1.53    2        6      29.2 ± 10.2                              140*              25       3      10 >30                                      144               500      5      83 ± 26.8                                145       0.25    1        6       >72                                        147*      1.9     5        6      15.9 ± 3.3                               149*      0.91    2        6      13.2 ± 1.9                               150       [9.3]** 10       6      25.5 ± 16.2                              151       5.1     10       3      67.3 ± 33.7                              ______________________________________                                         *Doryl conc. 1:10 million (instead of 1:5 million as in the other             instances)                                                                    **ED.sub.50                                                              

Cardiovascular Studies

The effect of a rapid intravenous injection on the heart rate the heartrate was conducted in anesthetized dogs under normal respiration. A fewopen-chest dogs were also tested. Increase in heart rate was measured byusing an electrocardiograph attached to the dog. Readings were takenevery 0.5-1 minute for the first 10 minutes and every 2-5 minutesthereafter until recovery. In some cases, several doses and more thanone compound were tested alternately in the same dog. The blood pressureeffect was simultaneously recorded. Tests carried out in this waydemonstrated that the esters of Formula I and Formula II had much lesscardiovascular stimulating effect than the corresponding unesterifiedphenols.

    ______________________________________                                        Effect on the Heart Rate                                                      in the Anesthetized Dog                                                                         Intravenous                                                                              Mean Maximal Increase                            Cpd of   No. of   Dose (salt)                                                                              in the Heart Rate                                Ex. No.  Dogs     mcg/kg     (Beats/Minute)                                                                           (%)                                   ______________________________________                                        135      3        0.25       5                                                         3        1          10                                                        3        8          17                                               139      1        5          6                                                                  25         28                                                                 50         35                                               149      2        0.8        19                                                        3        6.4        47                                                        1        32.0       70                                               151      1        32         18                                                                 128        24                                               148      1        6.5        32                                                                 32.5       58                                               30       4        70                    9                                              3        140                   15                                             3        280                   28                                    145      5        1.25                  9                                              5        5.0                   13                                             5        20                    27                                    Ref. Cpd. I                                                                            3        0.17                  20                                             4        0.35                  32                                             6        0.7                   44                                    Ref. Cpd. II                                                                           5        0.15                  26                                             5        0.3                   35                                             5        0.6                   50                                    Ref. Cpd. III                                                                          3        0.25       9                                                         3        1          15                                                        3        4          34                                               ______________________________________                                    

    ______________________________________                                        Effect on Diastolic Blood Pressure                                            in the Anesthetized Dog                                                                         Intravenous Mean Decrease in                                Cpd. of   No. of  Dose (salt) Diastolic Blood Pres-                           Ex. No.   Dogs    meg/kg      sure in %                                       ______________________________________                                        30        4       70          2                                                         3       140         11                                                        3       280         11.5                                            145       5       1.25        7                                                         5       5.0         12                                                        5       20          20                                              151       1       32          10                                                                128         10                                              Ref. Cpd. I                                                                             3       0.17        13                                                        4       0.35        33                                                        7       0.7         41                                              Ref. Cpd. II                                                                            6       0.15        12                                                        5       0.3         32                                                        7       0.6         40                                              ______________________________________                                    

We claim:
 1. A compound of the group consisting of: 3-(Y¹ -O-)-4-(Y-O-)phenyl (R-NH-)(R')methyl ketones having the formula ##STR6## and 3-(Y-O-CH₂ -)-4-(Y¹ -O-)phenyl (R-NH-) (R')methyl ketones having the formula ##STR7## .Iadd.wherein R, in Formula III, is tert-butyl or cycloalkyl having 3-6 carbon atoms; and in Formula IV is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms; and .Iaddend.wherein, in each formula: .[.R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;.]. R' is hydrogen or alkyl having 1-3 carbon atoms; Y' is hydrogen or an acyl member which is alkanoyl having 1-22 carbon atoms, cycloalkyl-C_(n) H_(2n) --CO-- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one, or two, 1- or 2-adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl, or Z--C_(n) H_(2n) --CO-- wherein n is zero, one or two and Z is phenyl or phenyl substituted by 1-3 members of the group consisting of alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, halo, or trifluoromethyl; Y is one of the acyl members defined by Y¹, at least one of Y and Y¹ being Z--C_(n) H_(2n) --CO--; and .[.wherein in Formula III at least one of Y and Y¹ contains no less than four carbon atoms when R is tert-butyl or cycloalkyl and no less than seven carbon atoms when R is hydrogen or alkyl other than tert-butyl; and in Formula IV at least one of Y and Y¹ contains no less than four carbon atoms; and.]. acid-addition salts thereof.
 2. A 3-(Y¹ -O-)-4-(Y-O)phenyl(R-NH-)(R')methyl ketone according to claim
 1. 3. A compound according to claim 2 wherein R' is hydrogen. .[.4. A compound according to claim 3 wherein R is alkyl..].
 5. A compound according to claim .[.4.]. .Iadd.3 .Iaddend.wherein R is tert-butyl.
 6. A 3-(Y-O-CH₂ -)-4-(Y¹ -O-)phenyl (R-NH-) (R')methyl ketone according to claim
 1. 7. A compound according to claim 6 wherein R' is hydrogen.
 8. A compound according to claim 7 wherein R is alkyl.
 9. A compound according to claim 8 wherein R is tert-butyl.
 10. A compound according to claim 9 wherein one of Y and Y¹ is alkanoyl.
 11. A compound according to claim 9 wherein Y¹ is hydrogen.
 12. A compound according to claim 5 wherein each of Y and Y¹ is Z-C_(n) H_(2n) --CO--.
 13. A compound according to claim 12 wherein n is zero.
 14. A compound according to claim 13 wherein each of Y and Y¹ is alkylbenzoyl.
 15. A compound according to claim 14 wherein each of Y and Y¹ is toluyl.
 16. A compound according to claim 13 wherein each of Y and Y¹ is anisoyl.
 17. A compound according to claim 5 wherein one of Y and Y¹ is alkanoyl and the other is Z--C_(n) H --CO--.
 18. A compound according to claim 17 wherein n is zero.
 19. A compound according to claim 18 wherein one of Y and Y¹ is alkylbenzoyl.
 20. A compound according to claim 19 wherein one of Y and Y¹ is toluyl.
 21. A compound according to claim 18 wherein one of Y and Y¹ is anisoyl. A compound according to claim 5 wherein Y¹ is hydrogen.
 23. A compound according to claim 22 wherein n is zero.
 24. A compound according to claim 23 wherein Y is toluyl.
 25. A compound according to claim 23 wherein Y is anisoyl.
 26. A compound according to claim 9 wherein each of Y and Y¹ is Z--C_(n) H_(2n) --CO--.
 27. A compound according to claim 26 wherein n is zero. 